Turn Back the TIMe: Targeting Tumor Infiltrating Myeloid Cells to Revert Cancer Progression

Frontiers in Immunology

Volumn 9, Issue , 2018, Pages

  Awad, Robin Maximilian ^a   De Vlaeminck, Yannick ^a   Maebe, Johannes ^a   Goyvaerts, Cleo ^a   Breckpot, Karine ^a  

^a VRIJE UNIVERSITEIT BRUSSEL   (Belgium)

Author keywords

cancer; dendritic cell; immature myeloid cell; macrophage; myeloid derived suppressor cell; tumor microenvironment

Indexed keywords

ANIMAL; BONE MARROW CELL; CARCINOGENESIS; CELL DIFFERENTIATION; CELL PROLIFERATION; DISEASE EXACERBATION; HUMAN; IMMUNOLOGY; IMMUNOTHERAPY; METASTASIS; NEOPLASM; PROCEDURES; TUMOR ESCAPE; TUMOR MICROENVIRONMENT;

ANIMALS; CARCINOGENESIS; CELL DIFFERENTIATION; CELL PROLIFERATION; DISEASE PROGRESSION; HUMANS; IMMUNOTHERAPY; MYELOID CELLS; NEOPLASM METASTASIS; NEOPLASMS; TUMOR ESCAPE; TUMOR MICROENVIRONMENT;

EID: 85055966641     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2018.01977     Document Type: Review

References (288)

1. Durgeau A Virk Y Corgnac S Mami-Chouaib F. Recent advances in targeting CD8 T-Cell immunity for more effective cancer immunotherapy. Front Immunol. (2018) 9:14. 10.3389/fimmu.2018.0001429403496
2. Binnewies M Roberts EW Kersten K Chan V Fearon DF Merad M et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. (2018) 24:541–50. 10.1038/s41591-018-0014-x29686425
3. De Vlaeminck Y Gonzalez-Rascon A Goyvaerts C Breckpot K. Cancer-associated myeloid regulatory cells. Front Immunol. (2016) 7:113. 10.3389/fimmu.2016.0011327065074
4. Mantovani A Allavena P Sica A Balkwill F. Cancer-related inflammation. Nature (2008) 454:436–44. 10.1038/nature0720518650914
5. Hanahan D Weinberg Robert A. Hallmarks of cancer: the next generation. Cell (2011) 144:646–74. 10.1016/j.cell.2011.02.01321376230
6. Dunn GP Old LJ Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. (2004) 22:329–60. 10.1146/annurev.immunol.22.012703.10480315032581
7. Franklin RA Liao W Sarkar A Kim MV Bivona MR Liu K et al. The cellular and molecular origin of tumor-associated macrophages. Science (2014) 344:921–5. 10.1126/science.125251024812208
8. Tymoszuk P Evens H Marzola V Wachowicz K Wasmer MH Datta S et al. In situ proliferation contributes to accumulation of tumor-associated macrophages in spontaneous mammary tumors. Eur J Immunol. (2014) 44:2247–62. 10.1002/eji.20134430424796276
9. Campbell MJ Tonlaar NY Garwood ER Huo D Moore DH Khramtsov AI et al. Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome. Breast Cancer Res Treat. (2011) 128:703–11. 10.1007/s10549-010-1154-y20842526
10. Veglia F Perego M Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol. (2018) 19:108–19. 10.1038/s41590-017-0022-x29348500
11. Zhou J Nefedova Y Lei A Gabrilovich D. Neutrophils and PMN-MDSC: Their biological role and interaction with stromal cells. Semin Immunol. (2018) 35:19–28. 10.1016/j.smim.2017.12.00429254756
12. Liechtenstein T Perez-Janices N Gato M Caliendo F Kochan G Blanco-Luquin I et al. A highly efficient tumor-infiltrating MDSC differentiation system for discovery of anti-neoplastic targets, which circumvents the need for tumor establishment in mice. Oncotarget (2014) 5:7843–57. 10.18632/oncotarget.227925151659
13. Kumar V Cheng P Condamine T Mony S Languino LR McCaffrey JC et al. CD45 phosphatase inhibits STAT3 transcription factor activity in myeloid cells and promotes tumor-associated macrophage differentiation. Immunity (2016) 44:303–15. 10.1016/j.immuni.2016.01.01426885857
14. Youn JI Kumar V Collazo M Nefedova Y Condamine T Cheng P et al. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat Immunol. (2013) 14:211–20. 10.1038/ni.252623354483
15. Singel KL Segal BH. Neutrophils in the tumor microenvironment: trying to heal the wound that cannot heal. Immunol Rev. (2016) 273:329–43. 10.1111/imr.1245927558344
16. Fridlender ZG Sun J Kim S Kapoor V Cheng G Ling L et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell (2009) 16:183–94. 10.1016/j.ccr.2009.06.01719732719
17. Keskinov AA Shurin MR. Myeloid regulatory cells in tumor spreading and metastasis. Immunobiology (2015) 220:236–42. 10.1016/j.imbio.2014.07.01725178934
18. Coffelt SB Wellenstein MD de Visser KE. Neutrophils in cancer: neutral no more. Nat Rev Cancer (2016) 16:431–46. 10.1038/nrc.2016.5227282249
19. Dehne N Mora J Namgaladze D Weigert A Brune B. Cancer cell and macrophage cross-talk in the tumor microenvironment. Curr Opin Pharmacol. (2017) 35:12–9. 10.1016/j.coph.2017.04.00728538141
20. Mills CD Shearer J Evans R Caldwell MD. Macrophage arginine metabolism and the inhibition or stimulation of cancer. J Immunol. (1992) 149:2709–14.
21. Mills CD. Anatomy of a Discovery: M1 and M2 Macrophages. Front Immunol. (2015) 6:212. 10.3389/fimmu.2015.0021225999950
22. Van den Bossche J Bogaert P van Hengel J Guerin CJ Berx G Movahedi K et al. Alternatively activated macrophages engage in homotypic and heterotypic interactions through IL-4 and polyamine-induced E-cadherin/catenin complexes. Blood (2009) 114:4664–74. 10.1182/blood-2009-05-22159819726720
23. Ghassabeh GH De Baetselier P Brys L Noel W Van Ginderachter JA Meerschaut S et al. Identification of a common gene signature for type II cytokine-associated myeloid cells elicited in vivo in different pathologic conditions. Blood (2006) 108:575–83. 10.1182/blood-2005-04-148516556895
24. Aras S Zaidi MR. TAMeless traitors: macrophages in cancer progression and metastasis. Br J Cancer (2017) 117:1583–91. 10.1038/bjc.2017.35629065107
25. Jinushi M Chiba S Yoshiyama H Masutomi K Kinoshita I Dosaka-Akita H et al. Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells. Proc Natl Acad Sci USA. (2011) 108:12425–30. 10.1073/pnas.110664510821746895
26. Jamieson AM Diefenbach A McMahon CW Xiong N Carlyle JR Raulet DH. The role of the NKG2D immunoreceptor in immune cell activation and natural killing. Immunity (2002) 17:19–29. 10.1016/S1074-7613(02)00333-312150888
27. Diefenbach A Jamieson AM Liu SD Shastri N Raulet DH. Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nat Immunol. (2000) 1:119–26. 10.1038/7779311248803
28. Bauer S Groh V Wu J Steinle A Phillips JH Lanier LL et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science (1999) 285:727–9. 10.1126/science.285.5428.72710426993
29. Iannello A Thompson TW Ardolino M Lowe SW Raulet DH. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J Exp Med. (2013) 210:2057–69. 10.1084/jem.2013078324043758
30. Kruse PH Matta J Ugolini S Vivier E. Natural cytotoxicity receptors and their ligands. Immunol Cell Biol. (2014) 92:221–9. 10.1038/icb.2013.9824366519
31. Bryceson YT March ME Barber DF Ljunggren HG Long EO. Cytolytic granule polarization and degranulation controlled by different receptors in resting NK cells. J Exp Med. (2005) 202:1001–12. 10.1084/jem.2005114316203869
32. Garrido F Algarra I. MHC antigens and tumor escape from immune surveillance. Adv Cancer Res. (2001) 83:117–58. 10.1016/S0065-230X(01)83005-011665717
33. Tu MM Mahmoud AB Wight A Mottashed A Belanger S Rahim MM et al. Ly49 family receptors are required for cancer immunosurveillance mediated by natural killer cells. Cancer Res. (2014) 74:3684–94. 10.1158/0008-5472.CAN-13-302124802191
34. Fernandez NC Lozier A Flament C Ricciardi-Castagnoli P Bellet D Suter M et al. Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nat Med. (1999) 5:405–11. 10.1038/740310202929
35. Chiba S Ikushima H Ueki H Yanai H Kimura Y Hangai S et al. Recognition of tumor cells by Dectin-1 orchestrates innate immune cells for anti-tumor responses. Elife (2014) 3:e04177. 10.7554/eLife.0417725149452
36. Ebihara T Azuma M Oshiumi H Kasamatsu J Iwabuchi K Matsumoto K et al. Identification of a polyI:C-inducible membrane protein that participates in dendritic cell–mediated natural killer cell activation. J Exp Med. (2010) 207:2675–87. 10.1084/jem.2009157321059856
37. Coulie PG Van den Eynde BJ van der Bruggen P Boon T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer (2014) 14:135–46. 10.1038/nrc367024457417
38. Markiewicz MA Carayannopoulos LN Naidenko OV Matsui K Burack WR Wise EL et al. Costimulation through NKG2D enhances murine CD8+ CTL function: similarities and differences between NKG2D and CD28 costimulation. J Immunol. (2005) 175:2825–33. 10.4049/jimmunol.175.5.282516116168
39. Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol. (2012) 23 (Suppl. 8):viii6–9. 10.1093/annonc/mds25622918931
40. Gardai SJ McPhillips KA Frasch SC Janssen WJ Starefeldt A Murphy-Ullrich JE et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell (2005) 123:321–34. 10.1016/j.cell.2005.08.03216239148
41. Diamond MS Kinder M Matsushita H Mashayekhi M Dunn GP Archambault JM et al. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J Exp Med. (2011) 208:1989–2003. 10.1084/jem.2010115821930769
42. Shen YJ Le Bert N Chitre AA Koo CX Nga XH Ho SS et al. Genome-derived cytosolic DNA mediates type I interferon-dependent rejection of B cell lymphoma cells. Cell Rep. (2015) 11:460–73. 10.1016/j.celrep.2015.03.04125865892
43. Chao MP Jaiswal S Weissman-Tsukamoto R Alizadeh AA Gentles AJ Volkmer J et al. Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci Transl Med. (2010) 2:63ra94. 10.1126/scitranslmed.300137521178137
44. Vicetti Miguel RD Cherpes TL Watson LJ McKenna KC. CTL induction of tumoricidal nitric oxide production by intratumoral macrophages is critical for tumor elimination. J Immunol. (2010) 185:6706–18. 10.4049/jimmunol.090341121041723
45. Corthay A Skovseth DK Lundin KU Rosjo E Omholt H Hofgaard PO et al. Primary antitumor immune response mediated by CD4+ T cells. Immunity (2005) 22:371–83. 10.1016/j.immuni.2005.02.00315780993
46. Matsushita H Vesely MD Koboldt DC Rickert CG Uppaluri R Magrini VJ et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature (2012) 482:400–4. 10.1038/nature1075522318521
47. von Boehmer L Mattle M Bode P Landshammer A Schafer C Nuber N et al. NY-ESO-1-specific immunological pressure and escape in a patient with metastatic melanoma. Cancer Immun. (2013) 13:12. 10.5167/uzh-7965723882157
48. Nicholaou T Chen W Davis ID Jackson HM Dimopoulos N Barrow C et al. Immunoediting and persistence of antigen-specific immunity in patients who have previously been vaccinated with NY-ESO-1 protein formulated in ISCOMATRIX. Cancer Immunol Immunother. (2011) 60:1625–37. 10.1007/s00262-011-1041-3
49. Tchou J Zhao Y Levine BL Zhang PJ Davis MM Melenhorst JJ et al. Safety and efficacy of intratumoral injections of chimeric antigen receptor (CAR) T cells in metastatic breast cancer. Cancer Immunol Res. (2017) 5:1152–61. 10.1158/2326-6066.CIR-17-018929109077
50. O'Sullivan T Saddawi-Konefka R Vermi W Koebel CM Arthur C White JM et al. Cancer immunoediting by the innate immune system in the absence of adaptive immunity. J Exp Med. (2012) 209:1869–82. 10.1084/jem.2011273822927549
51. Ahrends T Borst J. The opposing roles of CD4(+) T cells in anti-tumour immunity. Immunology (2018) 154. 10.1111/imm.1294129700809
52. Ben-Meir K Twaik N Baniyash M. Plasticity and biological diversity of myeloid derived suppressor cells. Curr Opin Immunol. (2018) 51:154–61. 10.1016/j.coi.2018.03.01529614426
53. Mittal D Gubin MM Schreiber RD Smyth MJ. New insights into cancer immunoediting and its three component phases–elimination, equilibrium and escape. Curr Opin Immunol. (2014) 27:16–25. 10.1016/j.coi.2014.01.00424531241
54. Krysko DV Garg AD Kaczmarek A Krysko O Agostinis P Vandenabeele P. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer (2012) 12:860–75. 10.1038/nrc338023151605
55. Braumuller H Wieder T Brenner E Assmann S Hahn M Alkhaled M et al. T-helper-1-cell cytokines drive cancer into senescence. Nature (2013) 494:361–5. 10.1038/nature1182423376950
56. Kursunel MA Esendagli G. The untold story of IFN-gamma in cancer biology. Cytokine Growth Factor Rev. (2016) 31:73–81. 10.1016/j.cytogfr.2016.07.00527502919
57. Yang H Lundback P Ottosson L Erlandsson-Harris H Venereau E Bianchi ME et al. Redox modification of cysteine residues regulates the cytokine activity of high mobility group box-1 (HMGB1). Mol Med. (2012) 18:250–9. 10.2119/molmed.2011.0038922105604
58. El-Kenawi A Ruffell B. Inflammation, ROS, and Mutagenesis. Cancer Cell. (2017) 32:727–9. 10.1016/j.ccell.2017.11.01529232551
59. Roca H Jones JD Purica MC Weidner S Koh AJ Kuo R et al. Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone. J Clin Invest. (2017) 128:248–66. 10.1172/JCI9246629202471
60. Tamadaho RSE Hoerauf A Layland LE. Immunomodulatory effects of myeloid-derived suppressor cells in diseases: Role in cancer and infections. Immunobiology (2018) 223:432–42. 10.1016/j.imbio.2017.07.00129246400
61. Mohamed E Al-Khami AA Rodriguez PC. The cellular metabolic landscape in the tumor milieu regulates the activity of myeloid infiltrates. Cell Mol Immunol. (2018) 15:421–7. 10.1038/s41423-018-0001-729568118
62. Schreiber RD Old LJ Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science (2011) 331:1565–70. 10.1126/science.120348621436444
63. Lin EY Gouon-Evans V Nguyen AV Pollard JW. The macrophage growth factor CSF-1 in mammary gland development and tumor progression. J Mammary Gland Biol Neoplasia (2002) 7:147–62. 10.1023/A:102039980279512465600
64. Zhang X Xue D Hao F Xie L He J Gai J et al. Remodeling and spacing factor 1 overexpression is associated with poor prognosis in renal cell carcinoma. Oncol Lett. (2018) 15:3852–7. 10.3892/ol.2018.779729467902
65. Chimal-Ramirez GK Espinoza-Sanchez NA Fuentes-Panana EM. Protumor activities of the immune response: insights in the mechanisms of immunological shift, oncotraining, and oncopromotion. J Oncol. (2013) 2013:835956. 10.1155/2013/83595623577028
66. Dufait I Van Valckenborgh E Menu E Escors D De Ridder M Breckpot K. Signal transducer and activator of transcription 3 in myeloid-derived suppressor cells: an opportunity for cancer therapy. Oncotarget (2016) 7:42698–715. 10.18632/oncotarget.831127029037
67. Kortylewski M Yu H. Role of Stat3 in suppressing anti-tumor immunity. Curr Opin Immunol. (2008) 20:228–33. 10.1016/j.coi.2008.03.01018479894
68. Arce F Breckpot K Stephenson H Karwacz K Ehrenstein MR Collins M et al. Selective ERK activation differentiates mouse and human tolerogenic dendritic cells, expands antigen-specific regulatory T cells, and suppresses experimental inflammatory arthritis. Arthritis Rheum. (2011) 63:84–95. 10.1002/art.3009920967853
69. Maenhout SK Van Lint S Emeagi PU Thielemans K Aerts JL. Enhanced suppressive capacity of tumor-infiltrating myeloid-derived suppressor cells compared with their peripheral counterparts. Int J Cancer (2014) 134:1077–90. 10.1002/ijc.2844923983191
70. Ballbach M Dannert A Singh A Siegmund DM Handgretinger R Piali L et al. Expression of checkpoint molecules on myeloid-derived suppressor cells. Immunol Lett. (2017) 192:1–6. 10.1016/j.imlet.2017.10.00128987474
71. Prima V Kaliberova LN Kaliberov S Curiel DT Kusmartsev S. COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells. Proc Natl Acad Sci USA. (2017) 114:1117–22. 10.1073/pnas.161292011428096371
72. Takahashi H Sakakura K Kudo T Toyoda M Kaira K Oyama T et al. Cancer-associated fibroblasts promote an immunosuppressive microenvironment through the induction and accumulation of protumoral macrophages. Oncotarget (2017) 8:8633–47. 10.18632/oncotarget.1437428052009
73. Chen J Ye Y Liu P Yu W Wei F Li H et al. Suppression of T cells by myeloid-derived suppressor cells in cancer. Hum Immunol. (2017) 78:113–9. 10.1016/j.humimm.2016.12.00127939507
74. Mougiakakos D Jitschin R von Bahr L Poschke I Gary R Sundberg B et al. Immunosuppressive CD14+HLA-DRlow/neg IDO+ myeloid cells in patients following allogeneic hematopoietic stem cell transplantation. Leukemia (2013) 27:377–88. 10.1038/leu.2012.21522828446
75. Yu J Du W Yan F Wang Y Li H Cao S et al. Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. J Immunol. (2013) 190:3783–97. 10.4049/jimmunol.1390024
76. Baratelli F Lin Y Zhu L Yang SC Heuze-Vourc'h N Zeng G et al. Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells. J Immunol. (2005) 175:1483–90. 10.4049/jimmunol.175.3.148316034085
77. Pan PY Ma G Weber KJ Ozao-Choy J Wang G Yin B et al. Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Res. (2010) 70:99–108. 10.1158/0008-5472.CAN-09-188219996287
78. Zoso A Mazza EM Bicciato S Mandruzzato S Bronte V Serafini P et al. Human fibrocytic myeloid-derived suppressor cells express IDO and promote tolerance via Treg-cell expansion. Eur J Immunol. (2014) 44:3307–19. 10.1002/eji.20144452225113564
79. Eruslanov EB Bhojnagarwala PS Quatromoni JG Stephen TL Ranganathan A Deshpande C et al. Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer. J Clin Invest. (2014) 124:5466–80. 10.1172/JCI7705325384214
80. Mancino A Schioppa T Larghi P Pasqualini F Nebuloni M Chen IH et al. Divergent effects of hypoxia on dendritic cell functions. Blood (2008) 112:3723–34. 10.1182/blood-2008-02-14209118694997
81. Elia AR Cappello P Puppo M Fraone T Vanni C Eva A et al. Human dendritic cells differentiated in hypoxia down-modulate antigen uptake and change their chemokine expression profile. J Leukoc Biol. (2008) 84:1472–82. 10.1189/jlb.020808218725395
82. Yang M Ma C Liu S Shao Q Gao W Song B et al. HIF-dependent induction of adenosine receptor A2b skews human dendritic cells to a Th2-stimulating phenotype under hypoxia. Immunol Cell Biol. (2010) 88:165–71. 10.1038/icb.2009.7719841638
83. Ghiringhelli F Puig PE Roux S Parcellier A Schmitt E Solary E et al. Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J Exp Med. (2005) 202:919–29. 10.1084/jem.2005046316186184
84. Munn DH Sharma MD Lee JR Jhaver KG Johnson TS Keskin DB et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science (2002) 297:1867–70. 10.1126/science.107351412228717
85. Mellor AL Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. (2004) 4:762–74. 10.1038/nri145715459668
86. Novitskiy SV Ryzhov S Zaynagetdinov R Goldstein AE Huang Y Tikhomirov OY et al. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood (2008) 112:1822–31. 10.1182/blood-2008-02-13632518559975
87. Liu Q Zhang C Sun A Zheng Y Wang L Cao X. Tumor-educated CD11bhighIalow regulatory dendritic cells suppress T cell response through arginase I. J Immunol. (2009) 182:6207–16. 10.4049/jimmunol.080392619414774
88. Albini A Bruno A Noonan DM Mortara L. Contribution to tumor angiogenesis from innate immune cells within the tumor microenvironment: implications for immunotherapy. Front Immunol. (2018) 9:527. 10.3389/fimmu.2018.0052729675018
89. Gordon-Weeks AN Lim SY Yuzhalin AE Jones K Markelc B Kim KJ et al. Neutrophils promote hepatic metastasis growth through fibroblast growth factor 2-dependent angiogenesis in mice. Hepatology (2017) 65:1920–35. 10.1002/hep.2908828133764
90. Tabaries S Ouellet V Hsu BE Annis MG Rose AA Meunier L et al. Granulocytic immune infiltrates are essential for the efficient formation of breast cancer liver metastases. Breast Cancer Res. (2015) 17:45. 10.1186/s13058-015-0558-325882816
91. Kowanetz M Wu X Lee J Tan M Hagenbeek T Qu X et al. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc Natl Acad Sci USA. (2010) 107:21248–55. 10.1073/pnas.101585510721081700
92. Shi H Zhang J Han X Li H Xie M Sun Y et al. Recruited monocytic myeloid-derived suppressor cells promote the arrest of tumor cells in the premetastatic niche through an IL-1beta-mediated increase in E-selectin expression. Int J Cancer. (2017) 140:1370–83. 10.1002/ijc.3053827885671
93. Safarzadeh E Orangi M Mohammadi H Babaie F Baradaran B. Myeloid-derived suppressor cells: Important contributors to tumor progression and metastasis. J Cell Physiol. (2018) 233:3024–36. 10.1002/jcp.2607528661031
94. Golden EB Frances D Pellicciotta I Demaria S Helen Barcellos-Hoff M Formenti SC. Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology (2014) 3:e28518. 10.4161/onci.2851825071979
95. Burnette BC Liang H Lee Y Chlewicki L Khodarev NN Weichselbaum RR et al. The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res. (2011) 71:2488–96. 10.1158/0008-5472.CAN-10-282021300764
96. Gupta A Probst HC Vuong V Landshammer A Muth S Yagita H et al. Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation. J Immunol. (2012) 189:558–66. 10.4049/jimmunol.120056322685313
97. Klug F Prakash H Huber PE Seibel T Bender N Halama N et al. Low-dose irradiation programs macrophage differentiation to an iNOS(+)/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell. (2013) 24:589–602. 10.1016/j.ccr.2013.09.01424209604
98. Formenti SC Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst. (2013) 105:256–65. 10.1093/jnci/djs62923291374
99. Russell JS Brown JM. The irradiated tumor microenvironment: role of tumor-associated macrophages in vascular recovery. Front Physiol. (2013) 4:157. 10.3389/fphys.2013.0015723882218
100. Vatner RE Formenti SC. Myeloid-derived cells in tumors: effects of radiation. Semin Radiat Oncol. (2015) 25:18–27. 10.1016/j.semradonc.2014.07.00825481262
101. Xu J Escamilla J Mok S David J Priceman S West B et al. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res. (2013) 73:2782–94. 10.1158/0008-5472.CAN-12-398123418320
102. Shiao SL Ruffell B DeNardo DG Faddegon BA Park CC Coussens LM. TH2-Polarized CD4(+) T cells and macrophages limit efficacy of radiotherapy. Cancer Immunol Res. (2015) 3:518–25. 10.1158/2326-6066.CIR-14-023225716473
103. Deng L Liang H Burnette B Beckett M Darga T Weichselbaum RR et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. (2014) 124:687–95. 10.1172/JCI6731324382348
104. Ma Y Galluzzi L Zitvogel L Kroemer G. Autophagy and cellular immune responses. Immunity (2013) 39:211–27. 10.1016/j.immuni.2013.07.01723973220
105. Pfirschke C Engblom C Rickelt S Cortez-Retamozo V Garris C Pucci F et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity (2016) 44:343–54. 10.1016/j.immuni.2015.11.02426872698
106. Miller MA Zheng YR Gadde S Pfirschke C Zope H Engblom C et al. Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug. Nat Commun. (2015) 6:8692. 10.1038/ncomms969226503691
107. Iida N Dzutsev A Stewart CA Smith L Bouladoux N Weingarten RA et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science (2013) 342:967–70. 10.1126/science.124052724264989
108. Vincent J Mignot G Chalmin F Ladoire S Bruchard M Chevriaux A et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. (2010) 70:3052–61. 10.1158/0008-5472.CAN-09-369020388795
109. DeNardo DG Brennan DJ Rexhepaj E Ruffell B Shiao SL Madden SF et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. (2011) 1:54–67. 10.1158/2159-8274.CD-10-002822039576
110. Bonapace L Coissieux MM Wyckoff J Mertz KD Varga Z Junt T et al. Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature (2014) 515:130–3. 10.1038/nature1386225337873
111. Shree T Olson OC Elie BT Kester JC Garfall AL Simpson K et al. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev. (2011) 25:2465–79. 10.1101/gad.180331.11122156207
112. Bruchard M Mignot G Derangere V Chalmin F Chevriaux A Vegran F et al. Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat Med. (2013) 19:57–64. 10.1038/nm.299923202296
113. Ruffell B Chang-Strachan D Chan V Rosenbusch A Ho CM Pryer N et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell (2014) 26:623–37. 10.1016/j.ccell.2014.09.00625446896
114. Mo HN Liu P. Targeting MET in cancer therapy. Chronic Dis Transl Med. (2017) 3:148–53. 10.1016/j.cdtm.2017.06.00229063069
115. Neuzillet C Tijeras-Raballand A Cohen R Cros J Faivre S Raymond E et al. Targeting the TGFbeta pathway for cancer therapy. Pharmacol Ther. (2015) 147:22–31. 10.1016/j.pharmthera.2014.11.00125444759
116. Cavnar MJ Zeng S Kim TS Sorenson EC Ocuin LM Balachandran VP et al. KIT oncogene inhibition drives intratumoral macrophage M2 polarization. J Exp Med. (2013) 210:2873–86. 10.1084/jem.2013087524323358
117. Hoeflich KP O'Brien C Boyd Z Cavet G Guerrero S Jung K et al. In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res. (2009) 15:4649–64. 10.1158/1078-0432.CCR-09-031719567590
118. McCubrey JA Steelman LS Chappell WH Abrams SL Wong EW Chang F et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta (2007) 1773:1263–84. 10.1016/j.bbamcr.2006.10.00117126425
119. Wan PT Garnett MJ Roe SM Lee S Niculescu-Duvaz D Good VM et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell (2004) 116:855–67. 10.1016/S0092-8674(04)00215-615035987
120. Zhang BH Guan KL. Activation of B-Raf kinase requires phosphorylation of the conserved residues Thr598 and Ser601. Embo J. (2000) 19:5429–39. 10.1093/emboj/19.20.542911032810
121. Steinberg SM Shabaneh TB Zhang P Martyanov V Li Z Malik BT et al. Myeloid cells that impair immunotherapy are restored in melanomas with acquired resistance to BRAF inhibitors. Cancer Res. (2017) 77:1599–610. 10.1158/0008-5472.CAN-16-175528202513
122. Smith MP Sanchez-Laorden B O'Brien K Brunton H Ferguson J Young H et al. The immune microenvironment confers resistance to MAPK pathway inhibitors through macrophage-derived TNFalpha. Cancer Discov. (2014) 4:1214–29. 10.1158/2159-8290.CD-13-100725256614
123. Mok S Tsoi J Koya RC Hu-Lieskovan S West BL Bollag G et al. Inhibition of colony stimulating factor-1 receptor improves antitumor efficacy of BRAF inhibition. BMC Cancer (2015) 15:356. 10.1186/s12885-015-1377-825939769
124. Ott PA Henry T Baranda SJ Frleta D Manches O Bogunovic D et al. Inhibition of both BRAF and MEK in BRAF(V600E) mutant melanoma restores compromised dendritic cell (DC) function while having differential direct effects on DC properties. Cancer Immunol Immunother. (2013) 62:811–22. 10.1007/s00262-012-1389-z23306863
125. Ott PA Bhardwaj N. Impact of MAPK pathway activation in BRAF(V600) melanoma on T cell and dendritic cell function. Front Immunol. (2013) 4:346. 10.3389/fimmu.2013.0034624194739
126. Finisguerra V Di Conza G Di Matteo M Serneels J Costa S Thompson AA et al. MET is required for the recruitment of anti-tumoural neutrophils. Nature (2015) 522:349–53. 10.1038/nature1440725985180
127. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer (2012) 12:252–64. 10.1038/nrc323922437870
128. Topalian SL Drake CG Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell (2015) 27:450–61. 10.1016/j.ccell.2015.03.00125858804
129. Sharma P Hu-Lieskovan S Wargo JA Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell (2017) 168:707–23. 10.1016/j.cell.2017.01.01728187290
130. Jenkins RW Barbie DA Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer (2018) 118:9–16. 10.1038/bjc.2017.43429319049
131. Meyer C Cagnon L Costa-Nunes CM Baumgaertner P Montandon N Leyvraz L et al. Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol Immunother. (2014) 63:247–57. 10.1007/s00262-013-1508-524357148
132. Bjoern J Juul Nitschke N Zeeberg Iversen T Schmidt H Fode K Svane IM. Immunological correlates of treatment and response in stage IV malignant melanoma patients treated with Ipilimumab. Oncoimmunology (2016) 5:e1100788. 10.1080/2162402X.2015.110078827141381
133. Highfill SL Cui Y Giles AJ Smith JP Zhang H Morse E et al. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med. (2014) 6:237ra67. 10.1126/scitranslmed.300797424848257
134. Orillion A Hashimoto A Damayanti NP Shen L Adelaiye-Ogala R Arisa S et al. Entinostat neutralizes myeloid derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma. Clin Cancer Res. (2017) 23:5187–201. 10.1158/1078-0432.CCR-17-074128698201
135. Kim K Skora AD Li Z Liu Q Tam AJ Blosser RL et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci. (2014) 111:11774. 10.1073/pnas.141062611125071169
136. Arlauckas SP Garris CS Kohler RH Kitaoka M Cuccarese MF Yang KS et al. In vivo imaging reveals a tumor-associated macrophage–mediated resistance pathway in anti–PD-1 therapy. Sci Trans Med. (2017) 9:eaal3604. 10.1126/scitranslmed.aal360428490665
137. Noman MZ Desantis G Janji B Hasmim M Karray S Dessen P et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. (2014) 211:781–90. 10.1084/jem.2013191624778419
138. Porta C Sica A Riboldi E. Tumor-associated myeloid cells: new understandings on their metabolic regulation and their influence in cancer immunotherapy. Febs J. (2018) 285:717–33. 10.1111/febs.1428828985035
139. Kuang DM Zhao Q Peng C Xu J Zhang JP Wu C et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med. (2009) 206:1327–37. 10.1084/jem.2008217319451266
140. Curiel TJ Wei S Dong H Alvarez X Cheng P Mottram P et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med. (2003) 9:562–7. 10.1038/nm86312704383
141. Spranger S Bao R Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature (2015) 523:231–5. 10.1038/nature1440425970248
142. Coffelt SB Kersten K Doornebal CW Weiden J Vrijland K Hau CS et al. IL-17-producing gammadelta T cells and neutrophils conspire to promote breast cancer metastasis. Nature (2015) 522:345–8. 10.1038/nature1428225822788
143. Srivastava MK Zhu L Harris-White M Kar UK Huang M Johnson MF et al. Myeloid suppressor cell depletion augments antitumor activity in lung cancer. PLoS ONE (2012) 7:e40677. 10.1371/annotation/5c756e7d-6e97-416f-836a-dced97cf46af22815789
144. Qian BZ Li J Zhang H Kitamura T Zhang J Campion LR et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature (2011) 475:222–5. 10.1038/nature1013821654748
145. Zhu Y Knolhoff BL Meyer MA Nywening TM West BL Luo J et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. (2014) 74:5057–69. 10.1158/0008-5472.CAN-13-372325082815
146. Ries CH Cannarile MA Hoves S Benz J Wartha K Runza V et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell (2014) 25:846–59. 10.1016/j.ccr.2014.05.01624898549
147. Strachan DC Ruffell B Oei Y Bissell MJ Coussens LM Pryer N et al. CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8(+) T cells. Oncoimmunology (2013) 2:e26968. 10.4161/onci.2696824498562
148. Mitchem JB Brennan DJ Knolhoff BL Belt BA Zhu Y Sanford DE et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. (2013) 73:1128–41. 10.1158/0008-5472.CAN-12-273123221383
149. Pyonteck SM Akkari L Schuhmacher AJ Bowman RL Sevenich L Quail DF et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. (2013) 19:1264–72. 10.1038/nm.333724056773
150. Chen X Wang Y Nelson D Tian S Mulvey E Patel B et al. CCL2/CCR2 regulates the tumor microenvironment in HER-2/neu-driven mammary carcinomas in mice. PLoS ONE (2016) 11:e0165595. 10.1371/journal.pone.016559527820834
151. Lesokhin AM Hohl TM Kitano S Cortez C Hirschhorn-Cymerman D Avogadri F et al. Monocytic CCR2(+) myeloid-derived suppressor cells promote immune escape by limiting activated CD8 T-cell infiltration into the tumor microenvironment. Cancer Res. (2012) 72:876–86. 10.1158/0008-5472.CAN-11-179222174368
152. Izhak L Wildbaum G Weinberg U Shaked Y Alami J Dumont D et al. Predominant expression of CCL2 at the tumor site of prostate cancer patients directs a selective loss of immunological tolerance to CCL2 that could be amplified in a beneficial manner. J Immunol. (2010) 184:1092–101. 10.4049/jimmunol.109002519995900
153. + macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma. Gut (2017) 67:1112–3. 10.1136/gutjnl-2017-313738
154. Ruffell B Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell. (2015) 27:462–72. 10.1016/j.ccell.2015.02.01525858805
155. Horikawa N Abiko K Matsumura N Hamanishi J Baba T Yamaguchi K et al. Expression of vascular endothelial growth factor in ovarian cancer inhibits tumor immunity through the accumulation of myeloid-derived suppressor cells. Clin Cancer Res. (2017) 23:587–99. 10.1158/1078-0432.CCR-16-038727401249
156. Linde N Lederle W Depner S van Rooijen N Gutschalk CM Mueller MM. Vascular endothelial growth factor-induced skin carcinogenesis depends on recruitment and alternative activation of macrophages. J Pathol. (2012) 227:17–28. 10.1002/path.398922262122
157. Avraham-Davidi I Yona S Grunewald M Landsman L Cochain C Silvestre JS et al. On-site education of VEGF-recruited monocytes improves their performance as angiogenic and arteriogenic accessory cells. J Exp Med. (2013) 210:2611–25. 10.1084/jem.2012069024166715
158. Chen XW Sun JG Zhang LP Liao XY Liao RX. Recruitment of CD11b(+)Ly6C(+) monocytes in non-small cell lung cancer xenografts challenged by anti-VEGF antibody. Oncol Lett. (2017) 14:615–22. 10.3892/ol.2017.623628693213
159. D'Agostino RB Sr. Changing end points in breast-cancer drug approval–the Avastin story. N Engl J Med. (2011) 365:e2. 10.1056/NEJMp110698421707384
160. Gilbert MR Dignam JJ Armstrong TS Wefel JS Blumenthal DT Vogelbaum MA et al. A randomized trial of bevacizumab for newly Diagnosed Glioblastoma. N Engl J Med. (2014) 370:699–708. 10.1056/NEJMoa130857324552317
161. Du Four S Maenhout SK Benteyn D De Keersmaecker B Duerinck J Thielemans K et al. Disease progression in recurrent glioblastoma patients treated with the VEGFR inhibitor axitinib is associated with increased regulatory T cell numbers and T cell exhaustion. Cancer Immunol Immunother. (2016) 65:727–40. 10.1007/s00262-016-1836-327098427
162. Heine A Held SA Daecke SN Riethausen K Kotthoff P Flores C et al. The VEGF-Receptor inhibitor axitinib impairs dendritic cell phenotype and function. PLoS ONE (2015) 10:e0128897. 10.1371/journal.pone.012889726042424
163. Du Four S Maenhout SK De Pierre K Renmans D Niclou SP Thielemans K et al. Axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intracranial mouse melanoma model. Oncoimmunology (2015) 4:e998107. 10.1080/2162402X.2014.99810726137411
164. Nishioka Y Hirao M Robbins PD Lotze MT Tahara H. Induction of systemic and therapeutic antitumor immunity using intratumoral injection of dendritic cells genetically modified to express interleukin 12. Cancer Res. (1999) 59:4035–41. 10463604
165. Mazzolini G Alfaro C Sangro B Feijoo E Ruiz J Benito A et al. Intratumoral injection of dendritic cells engineered to secrete interleukin-12 by recombinant adenovirus in patients with metastatic gastrointestinal carcinomas. J Clin Oncol. (2005) 23:999–1010. 10.1200/JCO.2005.00.46315598979
166. Stirewalt DL Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. (2003) 3:650–65. 10.1038/nrc116912951584
167. Watowich SS Liu YJ. Mechanisms regulating dendritic cell specification and development. Immunol Rev. (2010) 238:76–92. 10.1111/j.1600-065X.2010.00949.x20969586
168. Lynch DH Andreasen A Maraskovsky E Whitmore J Miller RE Schuh JC. Flt3 ligand induces tumor regression and antitumor immune responses in vivo. Nat Med. (1997) 3:625–31. 10.1038/nm0697-6259176488
169. Esche C Subbotin VM Maliszewski C Lotze MT Shurin MR. FLT3 ligand administration inhibits tumor growth in murine melanoma and lymphoma. Cancer Res. (1998) 58:380–3. 9458075
170. Hou S Kou G Fan X Wang H Qian W Zhang D et al. Eradication of hepatoma and colon cancer in mice with Flt3L gene therapy in combination with 5-FU. Cancer Immunol Immunother. (2007) 56:1605–13. 10.1007/s00262-007-0306-317361437
171. Tandon M Vemula SV Sharma A Ahi YS Mittal S Bangari DS et al. EphrinA1-EphA2 interaction-mediated apoptosis and Flt3L-induced immunotherapy inhibits tumor growth in a breast cancer mouse model. J Gene Med. (2012) 14:77–89. 10.1002/jgm.1649
172. Fong L Hou Y Rivas A Benike C Yuen A Fisher GA et al. Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc Natl Acad Sci USA. (2001) 98:8809–14. 10.1073/pnas.14122639811427731
173. Senzer NN Kaufman HL Amatruda T Nemunaitis M Reid T Daniels G et al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol. (2009) 27:5763–71. 10.1200/JCO.2009.24.367519884534
174. Kaufman HL Kim DW DeRaffele G Mitcham J Coffin RS Kim-Schulze S. Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Ann Surg Oncol. (2010) 17:718–30. 10.1245/s10434-009-0809-619915919
175. Liechtenstein T Perez-Janices N Blanco-Luquin I Goyvaerts C Schwarze J Dufait I et al. Anti-melanoma vaccines engineered to simultaneously modulate cytokine priming and silence PD-L1 characterized using ex vivo myeloid-derived suppressor cells as a readout of therapeutic efficacy. Oncoimmunology (2014) 3:e945378. 10.4161/21624011.2014.94537825954597
176. Dufait I Schwarze JK Liechtenstein T Leonard W Jiang H Escors D et al. Ex vivo generation of myeloid-derived suppressor cells that model the tumor immunosuppressive environment in colorectal cancer. Oncotarget. (2015) 6:12369–82. 10.18632/oncotarget.368225869209
177. De Santo C Salio M Masri SH Lee LY-H Dong T Speak AO et al. Invariant NKT cells reduce the immunosuppressive activity of influenza A virus–induced myeloid-derived suppressor cells in mice and humans. J Clin Invest. (2008) 118:4036–48. 10.1172/JCI3626419033672
178. Shirota Y Shirota H Klinman DM. Intratumoral injection of CpG oligonucleotides induces the differentiation and reduces the immunosuppressive activity of myeloid-derived suppressor cells. J Immunol. (2012) 188:1592–9. 10.4049/jimmunol.110130422231700
179. Takeda Y Kataoka K Yamagishi J Ogawa S Seya T Matsumoto M. A TLR3-specific adjuvant relieves innate resistance to PD-L1 blockade without cytokine toxicity in tumor vaccine immunotherapy. Cell Rep. (2017) 19:1874–87. 10.1016/j.celrep.2017.05.01528564605
180. Shime H Matsumoto M Seya T. Double-stranded RNA promotes CTL-independent tumor cytolysis mediated by CD11b(+)Ly6G(+) intratumor myeloid cells through the TICAM-1 signaling pathway. Cell Death Differ. (2017) 24:385–96. 10.1038/cdd.2016.13127834952
181. Zoglmeier C Bauer H Norenberg D Wedekind G Bittner P Sandholzer N et al. CpG blocks immunosuppression by myeloid-derived suppressor cells in tumor-bearing mice. Clin Cancer Res. (2011) 17:1765–75. 10.1158/1078-0432.CCR-10-267221233400
182. Shime H Matsumoto M Oshiumi H Tanaka S Nakane A Iwakura Y et al. Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors. Proc Natl Acad Sci USA. (2012) 109:2066–71. 10.1073/pnas.111309910922308357
183. Matsumoto M Tatematsu M Nishikawa F Azuma M Ishii N Morii-Sakai A et al. Defined TLR3-specific adjuvant that induces NK and CTL activation without significant cytokine production in vivo. Nat Commun. (2015) 6:6280. 10.1038/ncomms728025692975
184. Bunt SK Clements VK Hanson EM Sinha P Ostrand-Rosenberg S. Inflammation enhances myeloid-derived suppressor cell cross-talk by signaling through Toll-like receptor 4. J Leukoc Biol. (2009) 85:996–1004. 10.1189/jlb.070844619261929
185. Ko H-J Lee J-M Kim Y-J Kim Y-S Lee K-A Kang C-Y. Immunosuppressive myeloid-derived suppressor cells can be converted into immunogenic APCs with the help of activated NKT cells: an alternative cell-based antitumor vaccine. J Immunol. (2009) 182:1818–28. 10.4049/jimmunol.080243019201833
186. De Santo C Arscott R Booth S Karydis I Jones M Asher R et al. Invariant NKT cells modulate the suppressive activity of Serum Amyloid A-differentiated IL-10-secreting neutrophils. Nat Immunol. (2010) 11:1039–46. 10.1038/ni.1942
187. Beatty GL Chiorean EG Fishman MP Saboury B Teitelbaum UR Sun W et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science (2011) 331:1612–6. 10.1126/science.119844321436454
188. Beatty GL Torigian DA Chiorean EG Saboury B Brothers A Alavi A et al. A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin Cancer Res. (2013) 19:6286–95. 10.1158/1078-0432.CCR-13-132023983255
189. Cella M Scheidegger D Palmer-Lehmann K Lane P Lanzavecchia A Alber G. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med. (1996) 184:747–52. 10.1084/jem.184.2.7478760829
190. Scarlett UK Cubillos-Ruiz JR Nesbeth YC Martinez DG Engle X Gewirtz AT et al. In situ stimulation of CD40 and Toll-like receptor 3 transforms ovarian cancer-infiltrating dendritic cells from immunosuppressive to immunostimulatory cells. Cancer Res. (2009) 69:7329–37. 10.1158/0008-5472.CAN-09-083519738057
191. Van Lint S Renmans D Broos K Goethals L Maenhout S Benteyn D et al. Intratumoral delivery of TriMix mRNA results in T-cell activation by cross-presenting dendritic cells. Cancer Immunol Res. (2016) 4:146–56. 10.1158/2326-6066.CIR-15-016326659303
192. Cavallo F Giovarelli M Forni G Signorelli P Musiani P Modesti A et al. Antitumor efficacy of adenocarcinoma cells engineered to produce interleukin 12 (IL-12) or other cytokines compared with exogenous IL-12. JNCI. J Natl Cancer Inst. (1997) 89:1049–58. 10.1093/jnci/89.14.10499230887
193. Tanriover N Ulu MO Sanus GZ Bilir A Canbeyli R Oz B et al. The effects of systemic and intratumoral interleukin-12 treatment in C6 rat glioma model. Neurol Res. (2008) 30:511–7. 10.1179/174313208X28951618953742
194. Kerkar SP Goldszmid RS Muranski P Chinnasamy D Yu Z Reger RN et al. IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors. J Clin Invest. (2011) 121:4746–57. 10.1172/JCI5881422056381
195. Kerkar SP Restifo NP. The power and pitfalls of IL-12. Blood (2012) 119:4096. 10.1182/blood-2012-03-41501822555659
196. Watkins SK Egilmez NK Suttles J Stout RD. IL-12 rapidly alters the functional profile of tumor-associated and tumor-infiltrating macrophages in vitro and in vivo. J Immunol. (2007) 178:1357–62. 10.4049/jimmunol.178.3.135717237382
197. Haicheur N Escudier B Dorval T Negrier S De Mulder PH Dupuy JM et al. Cytokines and soluble cytokine receptor induction after IL-12 administration in cancer patients. Clin Exp Immunol. (2000) 119:28–37. 10.1046/j.1365-2249.2000.01112.x10606961
198. Portielje JE Lamers CH Kruit WH Sparreboom A Bolhuis RL Stoter G et al. Repeated administrations of interleukin (IL)-12 are associated with persistently elevated plasma levels of IL-10 and declining IFN-gamma, tumor necrosis factor-alpha, IL-6, and IL-8 responses. Clin Cancer Res. (2003) 9:76–83. 12538454
199. Yin XL Wang N Wei X Xie GF Li JJ Liang HJ. Interleukin-12 inhibits the survival of human colon cancer stem cells in vitro and their tumor initiating capacity in mice. Cancer Lett. (2012) 322:92–7. 10.1016/j.canlet.2012.02.01522366581
200. Gollob JA Mier JW Veenstra K McDermott DF Clancy D Clancy M et al. Phase I trial of twice-weekly intravenous interleukin 12 in patients with metastatic renal cell cancer or malignant melanoma: ability to maintain IFN-gamma induction is associated with clinical response. Clin Cancer Res. (2000) 6:1678–92. 10815886
201. Motzer RJ Rakhit A Schwartz LH Olencki T Malone TM Sandstrom K et al. Phase I trial of subcutaneous recombinant human interleukin-12 in patients with advanced renal cell carcinoma. Clin Cancer Res. (1998) 4:1183–91. 9607576
202. Cebon J Jager E Shackleton MJ Gibbs P Davis ID Hopkins W et al. Two phase I studies of low dose recombinant human IL-12 with Melan-A and influenza peptides in subjects with advanced malignant melanoma. Cancer Immun. (2003) 3:7. 12862418
203. Lorenzi S Mattei F Sistigu A Bracci L Spadaro F Sanchez M et al. Type I IFNs control antigen retention and survival of CD8alpha(+) dendritic cells after uptake of tumor apoptotic cells leading to cross-priming. J Immunol. (2011) 186:5142–50. 10.4049/jimmunol.100416321441457
204. Fuertes MB Kacha AK Kline J Woo SR Kranz DM Murphy KM et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ dendritic cells. J Exp Med. (2011) 208:2005–16. 10.1084/jem.2010115921930765
205. Picozzi VJ Abrams RA Decker PA Traverso W O'Reilly EM Greeno E et al. Multicenter phase II trial of adjuvant therapy for resected pancreatic cancer using cisplatin, 5-fluorouracil, and interferon-alfa-2b-based chemoradiation: ACOSOG Trial Z05031. Ann Oncol. (2011) 22:348–54. 10.1093/annonc/mdq38420670978
206. Van der Jeught K Joe PT Bialkowski L Heirman C Daszkiewicz L Liechtenstein T et al. Intratumoral administration of mRNA encoding a fusokine consisting of IFN-beta and the ectodomain of the TGF-beta receptor II potentiates antitumor immunity. Oncotarget (2014) 5:10100–13. 10.18632/oncotarget.246325338019
207. Tanikawa T Wilke CM Kryczek I Chen GY Kao J Nunez G et al. Interleukin-10 ablation promotes tumor development, growth, and metastasis. Cancer Res. (2012) 72:420–9. 10.1158/0008-5472.CAN-10-462722123924
208. Breckpot K Escors D. Dendritic cells for active anti-cancer immunotherapy: targeting activation pathways through genetic modification. Endocr Metab Immune Disord Drug Targets. (2009) 9:328–43. 10.2174/18715300978983915619857199
209. Arce F Kochan G Breckpot K Stephenson H Escors D. Selective activation of intracellular signalling pathways in dendritic cells for cancer immunotherapy. Anticancer Agents Med Chem. (2012) 12:29–39. 10.2174/18715201279876467921707504
210. Maenhout SK Du Four S Corthals J Neyns B Thielemans K Aerts JL. AZD1480 delays tumor growth in a melanoma model while enhancing the suppressive activity of myeloid-derived suppressor cells. Oncotarget (2014) 5:6801–15. 10.18632/oncotarget.225425149535
211. He W Zhu Y Mu R Xu J Zhang X Wang C et al. A Jak2-selective inhibitor potently reverses the immune suppression by modulating the tumor microenvironment for cancer immunotherapy. Biochem Pharmacol. (2017) 145:132–46. 10.1016/j.bcp.2017.08.01928859967
212. Spinetti T Spagnuolo L Mottas I Secondini C Treinies M Rüegg C et al. TLR7-based cancer immunotherapy decreases intratumoral myeloid–derived suppressor cells and blocks their immunosuppressive function. Oncoimmunology (2016) 5:e1230578. 10.1080/2162402X.2016.123057827999739
213. Kortylewski M Moreira D. Myeloid cells as a target for oligonucleotide therapeutics: turning obstacles into opportunities. Cancer Immunol Immunother. (2017) 66:979–88. 10.1007/s00262-017-1966-228214929
214. Fleming V Hu X Weber R Nagibin V Groth C Altevogt P et al. Targeting myeloid-derived suppressor cells to bypass tumor-induced immunosuppression. Front Immunol. (2018) 9:398. 10.3389/fimmu.2018.0039829552012
215. Luo Z Wang C Yi H Li P Pan H Liu L et al. Nanovaccine loaded with poly I:C and STAT3 siRNA robustly elicits anti-tumor immune responses through modulating tumor-associated dendritic cells in vivo. Biomaterials (2015) 38:50–60. 10.1016/j.biomaterials.2014.10.05025457983
216. Zhang Q Hossain DM Duttagupta P Moreira D Zhao X Won H et al. Serum-resistant CpG-STAT3 decoy for targeting survival and immune checkpoint signaling in acute myeloid leukemia. Blood (2016) 127:1687–700. 10.1182/blood-2015-08-66560426796361
217. Biswas SK Tergaonkar V. Myeloid differentiation factor 88-independent Toll-like receptor pathway: Sustaining inflammation or promoting tolerance? Int J Biochem Cell Biol. (2007) 39:1582–92. 10.1016/j.biocel.2007.04.021
218. Oshima H Oshima M Inaba K Taketo MM. Hyperplastic gastric tumors induced by activated macrophages in COX-2/mPGES-1 transgenic mice. Embo J. (2004) 23:1669–78. 10.1038/sj.emboj.760017015014433
219. Hagemann T Lawrence T McNeish I Charles KA Kulbe H Thompson RG et al. “Re-educating” tumor-associated macrophages by targeting NF-kappaB. J Exp Med. (2008) 205:1261–8. 10.1084/jem.2008010818490490
220. Thompson MG Larson M Vidrine A Barrios K Navarro F Meyers K et al. FOXO3-NF-kappaB RelA protein complexes reduce proinflammatory cell signaling and function. J Immunol. (2015) 195:5637–47. 10.4049/jimmunol.150175826561547
221. Breckpot K Aerts-Toegaert C Heirman C Peeters U Beyaert R Aerts JL et al. Attenuated expression of A20 markedly increases the efficacy of double-stranded RNA-activated dendritic cells as an anti-cancer vaccine. J Immunol. (2009) 182:860–70. 10.4049/jimmunol.182.2.86019124729
222. Kaneda MM Messer KS Ralainirina N Li H Leem CJ Gorjestani S et al. PI3Kgamma is a molecular switch that controls immune suppression. Nature (2016) 539:437–42. 10.1038/nature1983427642729
223. De Henau O Rausch M Winkler D Campesato LF Liu C Cymerman DH et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kgamma in myeloid cells. Nature (2016) 539:443–7. 10.1038/nature2055427828943
224. Covarrubias AJ Aksoylar HI Yu J Snyder NW Worth AJ Iyer SS et al. Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation. Elife (2016) 5:e11612. 10.7554/eLife.1161226894960
225. Nicodeme E Jeffrey KL Schaefer U Beinke S Dewell S Chung CW et al. Suppression of inflammation by a synthetic histone mimic. Nature (2010) 468:1119–23. 10.1038/nature0958921068722
226. Wang H Cheng F Woan K Sahakian E Merino O Rock-Klotz J et al. Histone deacetylase inhibitor LAQ824 augments inflammatory responses in macrophages through transcriptional regulation of IL-10. J Immunol. (2011) 186:3986–96. 10.4049/jimmunol.100110121368229
227. Chen X Barozzi I Termanini A Prosperini E Recchiuti A Dalli J et al. Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages. Proc Natl Acad Sci USA. (2012) 109:E2865–74. 10.1073/pnas.112113110922802645
228. Guerriero JL Sotayo A Ponichtera HE Castrillon JA Pourzia AL Schad S et al. Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature (2017) 543:428–32. 10.1038/nature2140928273064
229. Al-Khami AA Rodriguez PC Ochoa AC. Energy metabolic pathways control the fate and function of myeloid immune cells. J Leukoc Biol. (2017) 102:369–80. 10.1189/jlb.1VMR1216-535R28515225
230. Al-Khami AA Zheng L Del Valle L Hossain F Wyczechowska D Zabaleta J et al. Exogenous lipid uptake induces metabolic and functional reprogramming of tumor-associated myeloid-derived suppressor cells. Oncoimmunology (2017) 6:e1344804. 10.1080/2162402X.2017.134480429123954
231. Hossain F Al-Khami AA Wyczechowska D Hernandez C Zheng L Reiss K et al. Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies. Cancer Immunol Res. (2015) 3:1236–47. 10.1158/2326-6066.CIR-15-003626025381
232. Bougneres L Helft J Tiwari S Vargas P Chang BH Chan L et al. A role for lipid bodies in the cross-presentation of phagocytosed antigens by MHC class I in dendritic cells. Immunity (2009) 31:232–44. 10.1016/j.immuni.2009.06.02219699172
233. Herber DL Cao W Nefedova Y Novitskiy SV Nagaraj S Tyurin VA et al. Lipid accumulation and dendritic cell dysfunction in cancer. Nat Med. (2010) 16:880–6. 10.1038/nm.217220622859
234. Krawczyk CM Holowka T Sun J Blagih J Amiel E DeBerardinis RJ et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood (2010) 115:4742–9. 10.1182/blood-2009-10-24954020351312
235. Dong H Bullock TN. Metabolic influences that regulate dendritic cell function in tumors. Front Immunol. (2014) 5:24. 10.3389/fimmu.2014.0002424523723
236. Netea-Maier RT Smit JWA Netea MG. Metabolic changes in tumor cells and tumor-associated macrophages: a mutual relationship. Cancer Lett. (2018) 413:102–9. 10.1016/j.canlet.2017.10.03729111350
237. Geeraerts X Bolli E Fendt SM Van Ginderachter JA. Macrophage metabolism as therapeutic target for cancer, atherosclerosis, and obesity. Front Immunol. (2017) 8:289. 10.3389/fimmu.2017.0028928360914
238. Wenes M Shang M Di Matteo M Goveia J Martin-Perez R Serneels J et al. Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab. (2016) 24:701–15. 10.1016/j.cmet.2016.09.00827773694
239. Mills EL O'Neill LA. Reprogramming mitochondrial metabolism in macrophages as an anti-inflammatory signal. Eur J Immunol. (2016) 46:13–21. 10.1002/eji.20144542726643360
240. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer (2004) 4:71–8. 10.1038/nrc125614708027
241. Rotondo R Barisione G Mastracci L Grossi F Orengo AM Costa R et al. IL-8 induces exocytosis of arginase 1 by neutrophil polymorphonuclears in nonsmall cell lung cancer. Int J Cancer (2009) 125:887–93. 10.1002/ijc.2444819431148
242. Veglia F Gabrilovich DI. Dendritic cells in cancer: the role revisited. Curr Opin Immunol. (2017) 45:43–51. 10.1016/j.coi.2017.01.00228192720
243. Mbongue JC Nicholas DA Torrez TW Kim NS Firek AF Langridge WH. The role of indoleamine 2, 3-Dioxygenase in immune suppression and autoimmunity. Vaccines (2015) 3:703–29. 10.3390/vaccines303070326378585
244. Timosenko E Hadjinicolaou AV Cerundolo V. Modulation of cancer-specific immune responses by amino acid degrading enzymes. Immunotherapy (2017) 9:83–97. 10.2217/imt-2016-011828000524
245. Godin-Ethier J Hanafi LA Piccirillo CA Lapointe R. Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clin Cancer Res. (2011) 17:6985–91. 10.1158/1078-0432.CCR-11-133122068654
246. Manuel ER Diamond DJ. A road less traveled paved by IDO silencing: Harnessing the antitumor activity of neutrophils. Oncoimmunology (2013) 2. 10.4161/onci.2332223802075
247. Balachandran VP Cavnar MJ Zeng S Bamboat ZM Ocuin LM Obaid H et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med. (2011) 17:1094–100. 10.1038/nm.243821873989
248. von Bergwelt-Baildon MS Popov A Saric T Chemnitz J Classen S Stoffel MS et al. CD25 and indoleamine 2,3-dioxygenase are up-regulated by prostaglandin E2 and expressed by tumor-associated dendritic cells in vivo: additional mechanisms of T-cell inhibition. Blood (2006) 108:228–37. 10.1182/blood-2005-08-3507
249. Prendergast GC Smith C Thomas S Mandik-Nayak L Laury-Kleintop L Metz R et al. Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. Cancer Immunol Immunother. (2014) 63:721–35. 10.1007/s00262-014-1549-424711084
250. Hornyák L Dobos N Koncz G Karányi Z Páll D Szabó Z et al. The Role of Indoleamine-2,3-dioxygenase in cancer development, diagnostics, and therapy. Front Immunol. (2018) 9:151. 10.3389/fimmu.2018.0015129445380
251. Beatty GL O'Dwyer PJ Clark J Shi JG Bowman KJ Scherle PA et al. First-in-human phase I study of the oral inhibitor of indoleamine 2,3-Dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies. Clin Cancer Res. (2017) 23:3269–76. 10.1158/1078-0432.CCR-16-227228053021
252. Gangadhar TC Hamid O Smith DC Bauer TM Wasser JS Olszanski AJ et al. Epacadostat plus pembrolizumab in patients with advanced melanoma and select solid tumors: updated phase 1 results from ECHO-202/KEYNOTE-037. Ann Oncol. (2016) 27(Suppl. 6):1110PD. 10.1093/annonc/mdw379.06
253. Holmgaard RB Zamarin D Li Y Gasmi B Munn DH Allison JP et al. Tumor-expressed IDO recruits and activates MDSCs in a Treg-dependent manner. Cell Rep. (2015) 13:412–24. 10.1016/j.celrep.2015.08.07726411680
254. Metz R Rust S Duhadaway JB Mautino MR Munn DH Vahanian NN et al. IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan. Oncoimmunology (2012) 1:1460–8. 10.4161/onci.2171623264892
255. Sharma MD Hou DY Baban B Koni PA He Y Chandler PR et al. Reprogrammed Foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity (2010) 33:942–54. 10.1016/j.immuni.2010.11.02221145762
256. Mautino MR Kumar S Zhuang H Waldo J Jaipuri F Potturi H et al. Abstract 4076: a novel prodrug of indoximod with enhanced pharmacokinetic properties. Cancer Research. (2017) 77(13 Suppl.):4076. 10.1158/1538-7445.AM2017-4076
257. Vasquez-Dunddel D Pan F Zeng Q Gorbounov M Albesiano E Fu J et al. STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients. J Clin Invest. (2013) 123:1580–9. 10.1172/JCI6008323454751
258. Lang R Patel D Morris JJ Rutschman RL Murray PJ. Shaping gene expression in activated and resting primary macrophages by IL-10. J Immunol. (2002) 169:2253–63. 10.4049/jimmunol.169.5.225312193690
259. Boutard V Havouis R Fouqueray B Philippe C Moulinoux JP Baud L. Transforming growth factor-beta stimulates arginase activity in macrophages. Implications for the regulation of macrophage cytotoxicity. J Immunol. (1995) 155:2077–84. 7636258
260. Jost MM Ninci E Meder B Kempf C Van Royen N Hua J et al. Divergent effects of GM-CSF and TGFbeta1 on bone marrow-derived macrophage arginase-1 activity, MCP-1 expression, and matrix metalloproteinase-12: a potential role during arteriogenesis. Faseb J. (2003) 17:2281–3. 10.1096/fj.03-0071fje14525945
261. Corzo CA Condamine T Lu L Cotter MJ Youn JI Cheng P et al. HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med. (2010) 207:2439–53. 10.1084/jem.2010058720876310
262. de Boniface J Mao Y Schmidt-Mende J Kiessling R Poschke I. Expression patterns of the immunomodulatory enzyme arginase 1 in blood, lymph nodes and tumor tissue of early-stage breast cancer patients. Oncoimmunology (2012) 1:1305–12. 10.4161/onci.2167823243594
263. Yang Z Ming XF. Functions of arginase isoforms in macrophage inflammatory responses: impact on cardiovascular diseases and metabolic disorders. Front Immunol. (2014) 5:533. 10.3389/fimmu.2014.0053325386179
264. Toor SM Syed Khaja AS El Salhat H Bekdache O Kanbar J Jaloudi M et al. Increased levels of circulating and tumor-infiltrating granulocytic myeloid cells in colorectal cancer patients. Front Immunol. (2016) 7:560. 10.3389/fimmu.2016.0056028008330
265. Vannini F Kashfi K Nath N. The dual role of iNOS in cancer. Redox Biol. (2015) 6:334–43. 10.1016/j.redox.2015.08.00926335399
266. Rodriguez PC Ochoa AC Al-Khami AA. Arginine metabolism in myeloid cells shapes innate and adaptive immunity. Front Immunol. (2017) 8:93. 10.3389/fimmu.2017.0009328223985
267. Ochoa AC Zea AH Hernandez C Rodriguez PC. Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clin Cancer Res. (2007) 13(2 Pt 2):721s−6s. 10.1158/1078-0432.CCR-06-219717255300
268. Rodriguez PC Quiceno DG Zabaleta J Ortiz B Zea AH Piazuelo MB et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res. (2004) 64:5839–49. 10.1158/0008-5472.CAN-04-046515313928
269. Crittenden MR Savage T Cottam B Baird J Rodriguez PC Newell P et al. Expression of arginase I in myeloid cells limits control of residual disease after radiation therapy of tumors in mice. Radiat Res. (2014) 182:182–90. 10.1667/RR13493.124992164
270. Bronte V Kasic T Gri G Gallana K Borsellino G Marigo I et al. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J Exp Med. (2005) 201:1257–68. 10.1084/jem.2004202815824085
271. Serafini P Meckel K Kelso M Noonan K Califano J Koch W et al. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med. (2006) 203:2691–702. 10.1084/jem.2006110417101732
272. Meyer C Sevko A Ramacher M Bazhin AV Falk CS Osen W et al. Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model. Proc Natl Acad Sci USA. (2011) 108:17111–6. 10.1073/pnas.110812110821969559
273. Lin S Wang J Wang L Wen J Guo Y Qiao W et al. Phosphodiesterase-5 inhibition suppresses colonic inflammation-induced tumorigenesis via blocking the recruitment of MDSC. Am J Cancer Res. (2017) 7:41–52. 28123846
274. De Santo C Serafini P Marigo I Dolcetti L Bolla M Del Soldato P et al. Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination. Proc Natl Acad Sci USA. (2005) 102:4185–90. 10.1073/pnas.040978310215753302
275. Wesolowski R Markowitz J Carson WE III. Myeloid derived suppressor cells - a new therapeutic target in the treatment of cancer. J Immunother Cancer. (2013) 1:10. 10.1186/2051-1426-1-1024829747
276. Califano JA Khan Z Noonan KA Rudraraju L Zhang Z Wang H et al. Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res. (2015) 21:30–8. 10.1158/1078-0432.CCR-14-171625564570
277. Weed DT Vella JL Reis IM De la fuente AC Gomez C Sargi Z et al. Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell Carcinoma. Clin Cancer Res. (2015) 21:39–48. 10.1158/1078-0432.CCR-14-171125320361
278. Hassel JC Jiang H Bender C Winkler J Sevko A Shevchenko I et al. Tadalafil has biologic activity in human melanoma. Results of a pilot trial with Tadalafil in patients with metastatic Melanoma (TaMe). Oncoimmunology (2017) 6:e1326440. 10.1080/2162402X.2017.132644028932631
279. Kim SH Roszik J Grimm EA Ekmekcioglu S. Impact of l-arginine metabolism on immune response and anticancer immunotherapy. Front Oncol. (2018) 8:67. 10.3389/fonc.2018.0006729616189
280. Talmadge JE Hood KC Zobel LC Shafer LR Coles M Toth B. Chemoprevention by cyclooxygenase-2 inhibition reduces immature myeloid suppressor cell expansion. Int Immunopharmacol. (2007) 7:140–51. 10.1016/j.intimp.2006.09.02117178380
281. Eruslanov E Daurkin I Ortiz J Vieweg J Kusmartsev S. Pivotal Advance: Tumor-mediated induction of myeloid-derived suppressor cells and M2-polarized macrophages by altering intracellular PGE(2) catabolism in myeloid cells. J Leukoc Biol. (2010) 88:839–48. 10.1189/jlb.1209821
282. Obermajer N Muthuswamy R Lesnock J Edwards RP Kalinski P. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood (2011) 118:5498–505. 10.1182/blood-2011-07-36582521972293
283. Na YR Yoon YN Son DI Seok SH. Cyclooxygenase-2 inhibition blocks M2 macrophage differentiation and suppresses metastasis in murine breast cancer model. PLoS ONE. (2013) 8:e63451. 10.1371/journal.pone.006345123667623
284. Chen EP Markosyan N Connolly E Lawson JA Li X Grant GR et al. Myeloid Cell COX-2 deletion reduces mammary tumor growth through enhanced cytotoxic T-lymphocyte function. Carcinogenesis (2014) 35:1788–97. 10.1093/carcin/bgu05324590894
285. Zea AH Rodriguez PC Atkins MB Hernandez C Signoretti S Zabaleta J et al. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res. (2005) 65:3044–8. 10.1158/0008-5472.CAN-04-450515833831
286. Sinha P Clements VK Fulton AM Ostrand-Rosenberg S. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res. (2007) 67:4507–13. 10.1158/0008-5472.CAN-06-417417483367
287. Veltman JD Lambers ME van Nimwegen M Hendriks RW Hoogsteden HC Aerts JG et al. COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function. BMC Cancer (2010) 10:464. 10.1186/1471-2407-10-46420804550
288. Iachininoto MG Nuzzolo ER Bonanno G Mariotti A Procoli A Locatelli F et al. Cyclooxygenase-2 (COX-2) inhibition constrains indoleamine 2,3-dioxygenase 1 (IDO1) activity in acute myeloid leukaemia cells. Molecules (2013) 18:10132–45. 10.3390/molecules18091013223973990