Barriers to radiation-induced in situ tumor vaccination

Frontiers in Immunology

Volumn 8, Issue MAR, 2017, Pages

  Wennerberg, Erik ^a   Lhuillier, Claire ^a   Vanpouille Box, Claire ^a   Pilones, Karsten A ^a   García Martínez, Elena ^a,b   Rudqvist, Nils Petter ^a   Formenti, Silvia C ^a   Demaria, Sandra ^a  

^a WEILL CORNELL MEDICAL COLLEGE   (United States)

^b HOSPITAL MORALES MESEGUER   (Spain)

Author keywords

Abscopal effect; Adenosine; Hypoxia; Immunotherapy; Macrophages; Radiation therapy; Transforming growth factor ; Tumor microenvironment

Indexed keywords

5' NUCLEOTIDASE; ADENOSINE DIPHOSPHATE; ADENOSINE PHOSPHATE; ADENOSINE RECEPTOR 2A; ADENOSINE TRIPHOSPHATE; BEVACIZUMAB; CARLUMAB; CARRIER PROTEINS AND BINDING PROTEINS; CD39 ANTIGEN; CHEMOKINE RECEPTOR CCR2; COLONY STIMULATING FACTOR 1 RECEPTOR; FRESOLIMUMAB; GALUNISERTIB; HYPOXIA INDUCIBLE FACTOR 1ALPHA; INTERLEUKIN 10; INTERLEUKIN 18; INTERLEUKIN 1BETA; MONOCYTE CHEMOTACTIC PROTEIN 1; PROSTAGLANDIN E2; PURINERGIC RECEPTOR P2X 7; REACTIVE OXYGEN METABOLITE; SORAFENIB; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG; VASCULOTROPIN A; VASCULOTROPIN RECEPTOR; VASCULOTROPIN RECEPTOR 2;

CANCER IMMUNIZATION; CANCER PATIENT; CANCER RADIOTHERAPY; CLINICAL TRIAL (TOPIC); DENDRITIC CELL; HUMAN; IMMUNOGENICITY; IMMUNOSUPPRESSIVE TREATMENT; INTRACELLULAR SIGNALING; MACROPHAGE; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHENOTYPE; PROTEIN EXPRESSION; REVIEW; TUMOR ASSOCIATED LEUKOCYTE;

EID: 85017268441     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2017.00229     Document Type: Review

References (135)

1. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol (2013) 14(10):1014-22. doi: 10.1038/ni.2703
2. Formenti SC, Demaria S. Radiation therapy to convert the tumor into an in situ vaccine. Int J Radiat Oncol Biol Phys (2012) 84(4):879-80. doi:10.1016/j.ijrobp.2012.06.020
3. Kepp O, Tesniere A, Schlemmer F, Michaud M, Senovilla L, Zitvogel L, et al. Immunogenic cell death modalities and their impact on cancer treatment. Apoptosis (2009) 14(4):364-75. doi:10.1007/s10495-008-0303-9
4. Frey B, Hehlgans S, Rödel F, Gaipl US. Modulation of inflammation by low and high doses of ionizing radiation: implications for benign and malign diseases. Cancer Lett (2015) 368(2):230-7. doi:10.1016/j.canlet.2015.04.010
5. 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. doi:10.4161/onci.28518
6. Ma Y, Adjemian S, Yang H, Catani JP, Hannani D, Martins I, et al. ATP-dependent recruitment, survival and differentiation of dendritic cell precursors in the tumor bed after anticancer chemotherapy. Oncoimmunology (2013) 2(6):e24568. doi:10.4161/onci.24568
7. Gameiro SR, Jammeh ML, Wattenberg MM, Tsang KY, Ferrone S, Hodge JW. Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget (2014) 5(2):403-16. doi:10.18632/oncotarget.1719
8. Kulzer L, Rubner Y, Deloch L, Allgäuer A, Frey B, Fietkau R, et al. Norm-and hypo-fractionated radiotherapy is capable of activating human dendritic cells. J Immunotoxicol (2014) 11(4):328-36. doi:10.3109/1547691X.2014.880533
9. Apetoh L, Ghiringhelli F, Tesniere A, Criollo A, Ortiz C, Lidereau R, et al. The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev (2007) 220:47-59. doi:10.1111/j.1600-065X.2007.00573.x
10. Matsumura S, Wang B, Kawashima N, Braunstein S, Badura M, Cameron TO, et al. Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells. J Immunol (2008) 181(5):3099-107. doi:10.4049/jimmunol.181.5.3099
11. Lim JY, Gerber SA, Murphy SP, Lord EM. Type I interferons induced by radiation therapy mediate recruitment and effector function of CD8(+) T cells. Cancer Immunol Immunother (2014) 63(3):259-71. doi:10.1007/s00262-013-1506-7
12. Sridharan V, Margalit DN, Lynch SA, Severgnini M, Zhou J, Chau NG, et al. Definitive chemoradiation alters the immunologic landscape and immune checkpoints in head and neck cancer. Br J Cancer (2016) 115(2):252-60. doi:10.1038/bjc.2016.166
13. Lugade AA, Sorensen EW, Gerber SA, Moran JP, Frelinger JG, Lord EM. Radiation-induced IFN-gamma production within the tumor microenvironment influences antitumor immunity. J Immunol (2008) 180(5):3132-9. doi:10.4049/jimmunol.180.5.3132
14. Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med (2006) 203(5):1259-71. doi:10.1084/jem.20052494
15. Chakraborty M, Abrams SI, Camphausen K, Liu K, Scott T, Coleman CN, et al. Irradiation of tumor cells up-regulates Fas and enhances CTL lytic activity and CTL adoptive immunotherapy. J Immunol (2003) 170(12):6338-47. doi:10.4049/jimmunol.170.12.6338
16. Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys (2004) 58(3):862-70. doi:10.1016/j.ijrobp.2003.09.012
17. Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res (2009) 15(17):5379-88. doi:10.1158/1078-0432.CCR-09-0265
18. Golden EB, Demaria S, Schiff PB, Chachoua A, Formenti SC. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res (2013) 1(6):365-72. doi:10.1158/2326-6066.CIR-13-0115
19. Brody JD, Ai WZ, Czerwinski DK, Torchia JA, Levy M, Advani RH, et al. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. J Clin Oncol (2010) 28(28):4324-32. doi:10.1200/JCO.2010.28.9793
20. Golden EB, Chhabra A, Chachoua A, Adams S, Donach M, Fenton-Kerimian M, et al. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol (2015) 16(7):795-803. doi:10.1016/S1470-2045(15)00054-6
21. Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med (2012) 366(10):925-31. doi:10.1056/NEJMoa1112824
22. 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. doi:10.1016/j.coi.2014.01.004
23. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature (2015) 523(7559):231-5. doi:10.1038/nature14404
24. 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(9):2782-94. doi:10.1158/0008-5472.CAN-12-3981
25. Frenguelli BG, Wigmore G, Llaudet E, Dale N. Temporal and mechanistic dissociation of ATP and adenosine release during ischaemia in the mammalian hippocampus. J Neurochem (2007) 101(5):1400-13. doi:10.1111/j.1471-4159.2007.04425.x
26. Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol (2002) 196(3):254-65. doi:10.1002/path.1027
27. O'Shea JJ, Murray PJ. Cytokine signaling modules in inflammatory responses. Immunity (2008) 28(4):477-87. doi:10.1016/j.immuni.2008.03.002
28. 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(7355):222-5. doi:10.1038/nature10138
29. Qian B, Deng Y, Im JH, Muschel RJ, Zou Y, Li J, et al. A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS One (2009) 4(8):e6562. doi:10.1371/journal.pone.0006562
30. Pollard JW. Macrophages define the invasive microenvironment in breast cancer. J Leukoc Biol (2008) 84(3):623-30. doi:10.1189/jlb.1107762
31. Lin EY, Li JF, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA, et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res (2006) 66(23):11238-46. doi:10.1158/0008-5472.CAN-06-1278
32. Vatner RE, Formenti SC. Myeloid-derived cells in tumors: effects of radiation. Semin Radiat Oncol (2015) 25(1):18-27. doi:10.1016/j.semradonc.2014.07.008
33. 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(5):589-602. doi:10.1016/j.ccr.2013.09.014
34. Hamilton JA. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol (2008) 8(7):533-44. doi:10.1038/nri2356
35. Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol (2006) 18(1):39-48. doi:10.1016/j.coi.2005.11.006
36. Priceman SJ, Sung JL, Shaposhnik Z, Burton JB, Torres-Collado AX, Moughon DL, et al. Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy. Blood (2010) 115(7):1461-71. doi:10.1182/blood-2009-08-237412
37. 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(1):54-67. doi:10.1158/2159-8274.CD-10-0028
38. 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(2):147-62. doi:10.1023/A:1020399802795
39. Sharma M, Beck AH, Webster JA, Espinosa I, Montgomery K, Varma S, et al. Analysis of stromal signatures in the tumor microenvironment of ductal carcinoma in situ. Breast Cancer Res Treat (2010) 123(2):397-404. doi:10.1007/s10549-009-0654-0
40. Beck AH, Espinosa I, Edris B, Li R, Montgomery K, Zhu S, et al. The macrophage colony-stimulating factor 1 response signature in breast carcinoma. Clin Cancer Res (2009) 15(3):778-87. doi:10.1158/1078-0432.CCR-08-1283
41. Kalbasi A, Komar C, Tooker GM, Liu M, Lee JW, Gladney WL, et al. Tumor-derived CCL2 mediates resistance to radiotherapy in pancreatic ductal adenocarcinoma. Clin Cancer Res (2017) 23(1):137-48. doi:10.1158/1078-0432.CCR-16-0870
42. Sanford DE, Belt BA, Panni RZ, Mayer A, Deshpande AD, Carpenter D, et al. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin Cancer Res (2013) 19(13):3404-15. doi:10.1158/1078-0432.CCR-13-0525
43. Li X, Yao W, Yuan Y, Chen P, Li B, Li J, et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut (2017) 66(1):157-67. doi:10.1136/gutjnl-2015-310514
44. Pienta KJ, Machiels JP, Schrijvers D, Alekseev B, Shkolnik M, Crabb SJ, et al. Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer. Invest New Drugs (2013) 31(3):760-8. doi:10.1007/s10637-012-9869-8
45. Gilbert J, Lekstrom-Himes J, Donaldson D, Lee Y, Hu M, Xu J, et al. Effect of CC chemokine receptor 2 CCR2 blockade on serum C-reactive protein in individuals at atherosclerotic risk and with a single nucleotide polymorphism of the monocyte chemoattractant protein-1 promoter region. Am J Cardiol (2011) 107(6):906-11. doi:10.1016/j.amjcard.2010.11.005
46. de Zeeuw D, Bekker P, Henkel E, Hasslacher C, Gouni-Berthold I, Mehling H, et al. The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial. Lancet Diabetes Endocrinol (2015) 3(9):687-96. doi:10.1016/S2213-8587(15)00261-2
47. Ishikawa H, Sakurai H, Hasegawa M, Mitsuhashi N, Takahashi M, Masuda N, et al. Expression of hypoxic-inducible factor 1alpha predicts metastasis-free survival after radiation therapy alone in stage IIIB cervical squamous cell carcinoma. Int J Radiat Oncol Biol Phys (2004) 60(2):513-21. doi:10.1016/j.ijrobp.2004.03.025
48. Aebersold DM, Burri P, Beer KT, Laissue J, Djonov V, Greiner RH, et al. Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res (2001) 61(7):2911-6.
49. Moeller BJ, Cao Y, Li CY, Dewhirst MW. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell (2004) 5(5):429-41. doi:10.1016/S1535-6108(04)00115-1
50. Kim YH, Yoo KC, Cui YH, Uddin N, Lim EJ, Kim MJ, et al. Radiation promotes malignant progression of glioma cells through HIF-1alpha stabilization. Cancer Lett (2014) 354(1):132-41. doi:10.1016/j.canlet.2014.07.048
51. 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(5):781-90. doi:10.1084/jem.20131916
52. Barsoum IB, Smallwood CA, Siemens DR, Graham CH. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res (2014) 74(3):665-74. doi:10.1158/0008-5472.CAN-13-0992
53. Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature (2011) 475(7355):226-30. doi:10.1038/nature10169
54. Doedens AL, Stockmann C, Rubinstein MP, Liao D, Zhang N, DeNardo DG, et al. Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Res (2010) 70(19):7465-75. doi:10.1158/0008-5472.CAN-10-1439
55. Laoui D, Van Overmeire E, Di Conza G, Aldeni C, Keirsse J, Morias Y, et al. Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. Cancer Res (2014) 74(1):24-30. doi:10.1158/0008-5472.CAN-13-1196
56. Corzo CA, Thomas C, Lily L, Matthew JC, Je-In Y, Pingyan C, et al. HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med (2010) 207(11):2439-53. doi:10.1084/jem.20100587
57. Sceneay J, Chow MT, Chen A, Halse HM, Wong CS, Andrews DM, et al. Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+ immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche. Cancer Res (2012) 72(16):3906-11. doi:10.1158/0008-5472.CAN-11-3873
58. Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, et al. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature (1998) 394(6692):485-90. doi:10.1038/28867
59. Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegué E, et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell (2008) 13(3):206-20. doi:10.1016/j.ccr.2008.01.034
60. Ahn GO, Seita J, Hong BJ, Kim YE, Bok S, Lee CJ, et al. Transcriptional activation of hypoxia-inducible factor-1 (HIF-1) in myeloid cells promotes angiogenesis through VEGF and S100A8. Proc Natl Acad Sci U S A (2014) 111(7):2698-703. doi:10.1073/pnas.1320243111
61. Lund EL, Høg A, Olsen MW, Hansen LT, Engelholm SA, Kristjansen PE. Differential regulation of VEGF, HIF1alpha and angiopoietin-1,-2 and-4 by hypoxia and ionizing radiation in human glioblastoma. Int J Cancer (2004) 108(6):833-8. doi:10.1002/ijc.11662
62. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev (1997) 18(1):4-25. doi:10.1210/edrv.18.1.0287
63. Terme M, Pernot S, Marcheteau E, Sandoval F, Benhamouda N, Colussi O, et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res (2013) 73(2):539-49. doi:10.1158/0008-5472.CAN-12-2325
64. Suzuki H, Onishi H, Wada J, Yamasaki A, Tanaka H, Nakano K, et al. VEGFR2 is selectively expressed by FOXP3high CD4+ Treg. Eur J Immunol (2010) 40(1):197-203. doi:10.1002/eji.200939887
65. Huang Y, Chen X, Dikov MM, Novitskiy SV, Mosse CA, Yang L, et al. Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF. Blood (2007) 110(2):624-31. doi:10.1182/blood-2007-01-065714
66. Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood (1998) 92(11):4150-66.
67. 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(2):587-99. doi:10.1158/1078-0432.CCR-16-0387
68. Ziogas AC, Gavalas NG, Tsiatas M, Tsitsilonis O, Politi E, Terpos E, et al. VEGF directly suppresses activation of T cells from ovarian cancer patients and healthy individuals via VEGF receptor type 2. Int J Cancer (2012) 130(4):857-64. doi:10.1002/ijc.26094
69. Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med (2015) 212(2):139-48. doi:10.1084/jem.20140559
70. Motz GT, Santoro SP, Wang LP, Garrabrant T, Lastra RR, Hagemann IS, et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med (2014) 20(6):607-15. doi:10.1038/nm.3541
71. Gorski DH, Beckett MA, Jaskowiak NT, Calvin DP, Mauceri HJ, Salloum RM, et al. Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res (1999) 59(14):3374-8.
72. Geng L, Donnelly E, McMahon G, Lin PC, Sierra-Rivera E, Oshinka H, et al. Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res (2001) 61(6):2413-9.
73. Allard B, Beavis PA, Darcy PK, Stagg J. Immunosuppressive activities of adenosine in cancer. Curr Opin Pharmacol (2016) 29:7-16. doi:10.1016/j.coph.2016.04.001
74. Sitkovsky MV, Lukashev D, Apasov S, Kojima H, Koshiba M, Caldwell C, et al. Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu Rev Immunol (2004) 22:657-82. doi:10.1146/annurev.immunol.22.012703.104731
75. Ma Y, Adjemian S, Mattarollo SR, Yamazaki T, Aymeric L, Yang H, et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity (2013) 38(4):729-41. doi:10.1016/j.immuni.2013.03.003
76. Gombault A, Baron L, Couillin I. ATP release and purinergic signaling in NLRP3 inflammasome activation. Front Immunol (2013) 3:414. doi:10.3389/fimmu.2012.00414
77. Kepp O, Galluzzi L, Martins I, Schlemmer F, Adjemian S, Michaud M, et al. Molecular determinants of immunogenic cell death elicited by anticancer chemotherapy. Cancer Metastasis Rev (2011) 30(1):61-9. doi:10.1007/s10555-011-9273-4
78. Aymeric L, Apetoh L, Ghiringhelli F, Tesniere A, Martins I, Kroemer G, et al. Tumor cell death and ATP release prime dendritic cells and efficient anticancer immunity. Cancer Res (2010) 70(3):855-8. doi:10.1158/0008-5472.CAN-09-3566
79. Deaglio S, Robson SC. Ectonucleotidases as regulators of purinergic signaling in thrombosis, inflammation, and immunity. Adv Pharmacol (2011) 61:301-32. doi:10.1016/B978-0-12-385526-8.00010-2
80. Palmer TM, Trevethick MA. Suppression of inflammatory and immune responses by the A(2A) adenosine receptor: an introduction. Br J Pharmacol (2008) 153(Suppl 1):S27-34. doi:10.1038/sj.bjp.0707524
81. Ohta A, Kini R, Ohta A, Subramanian M, Madasu M, Sitkovsky M. The development and immunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway. Front Immunol (2012) 3:190. doi:10.3389/fimmu.2012.00190
82. Cekic C, Day YJ, Sag D, Linden J. Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment. Cancer Res (2014) 74(24):7250-9. doi:10.1158/0008-5472.CAN-13-3583
83. Ahmad A, Ahmad S, Glover L, Miller SM, Shannon JM, Guo X, et al. Adenosine A2A receptor is a unique angiogenic target of HIF-2alpha in pulmonary endothelial cells. Proc Natl Acad Sci U S A (2009) 106(26):10684-9. doi:10.1073/pnas.0901326106
84. Loi S, Pommey S, Haibe-Kains B, Beavis PA, Darcy PK, Smyth MJ, et al. CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. Proc Natl Acad Sci U S A (2013) 110(27):11091-6. doi:10.1073/pnas.1222251110
85. Lu XX, Chen YT, Feng B, Mao XB, Yu B, Chu XY. Expression and clinical significance of CD73 and hypoxia-inducible factor-1alpha in gastric carcinoma. World J Gastroenterol (2013) 19(12):1912-8. doi:10.3748/wjg.v19.i12.1912
86. Wu XR, He XS, Chen YF, Yuan RX, Zeng Y, Lian L, et al. High expression of CD73 as a poor prognostic biomarker in human colorectal cancer. J Surg Oncol (2012) 106(2):130-7. doi:10.1002/jso.23056
87. Xiong L, Wen Y, Miao X, Yang Z. NT5E and FcGBP as key regulators of TGF-1-induced epithelial-mesenchymal transition (EMT) are associated with tumor progression and survival of patients with gallbladder cancer. Cell Tissue Res (2014) 355(2):365-74. doi:10.1007/s00441-013-1752-1
88. Stagg J, Divisekera U, Duret H, Sparwasser T, Teng MW, Darcy PK, et al. CD73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis. Cancer Res (2011) 71(8):2892-900. doi:10.1158/0008-5472.CAN-10-4246
89. Bastid J, Regairaz A, Bonnefoy N, Déjou C, Giustiniani J, Laheurte C, et al. Inhibition of CD39 enzymatic function at the surface of tumor cells alleviates their immunosuppressive activity. Cancer Immunol Res (2015) 3(3):254-65. doi:10.1158/2326-6066.CIR-14-0018
90. Umansky V, Shevchenko I, Bazhin AV, Utikal J. Extracellular adenosine metabolism in immune cells in melanoma. Cancer Immunol Immunother (2014) 63(10):1073-80. doi:10.1007/s00262-014-1553-8
91. Mandapathil M, Hilldorfer B, Szczepanski MJ, Czystowska M, Szajnik M, Ren J, et al. Generation and accumulation of immunosuppressive adenosine by human CD4+CD25highFOXP3+ regulatory T cells. J Biol Chem (2010) 285(10):7176-86. doi:10.1074/jbc.M109.047423
92. Knapp K, Zebisch M, Pippel J, El-Tayeb A, Müller CE, Sträter N. Crystal structure of the human ecto-5'-nucleotidase (CD73): insights into the regulation of purinergic signaling. Structure (2012) 20(12):2161-73. doi:10.1016/j.str.2012.10.001
93. Strater N. Ecto-5'-nucleotidase: structure function relationships. Purinergic Signal (2006) 2(2):343-50. doi:10.1007/s11302-006-9000-8
94. Whiteside TL, Mandapathil M, Schuler P. The role of the adenosinergic pathway in immunosuppression mediated by human regulatory T cells (Treg). Curr Med Chem (2011) 18(34):5217-23. doi:10.2174/092986711798184334
95. Hyman MC, Petrovic-Djergovic D, Visovatti SH, Liao H, Yanamadala S, Bouïs D, et al. Self-regulation of inflammatory cell trafficking in mice by the leukocyte surface apyrase CD39. J Clin Invest (2009) 119(5):1136-49. doi:10.1172/JCI36433
96. Chen Y, Yao Y, Sumi Y, Li A, To UK, Elkhal A, et al. Purinergic signaling: a fundamental mechanism in neutrophil activation. Sci Signal (2010) 3(125):ra45. doi:10.1126/scisignal.2000549
97. Ryzhov S, Novitskiy SV, Goldstein AE, Biktasova A, Blackburn MR, Biaggioni I, et al. Adenosinergic regulation of the expansion and immunosuppressive activity of CD11b+Gr1+ cells. J Immunol (2011) 187(11):6120-9. doi:10.4049/jimmunol.1101225
98. Allard B, Pommey S, Smyth MJ, Stagg J. Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin Cancer Res (2013) 19(20):5626-35. doi:10.1158/1078-0432.CCR-13-0545
99. Beavis PA, Milenkovski N, Henderson MA, John LB, Allard B, Loi S, et al. Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T-cell responses. Cancer Immunol Res (2015) 3(5):506-17. doi:10.1158/2326-6066.CIR-14-0211
100. Iannone R, Miele L, Maiolino P, Pinto A, Morello S. Adenosine limits the therapeutic effectiveness of anti-CTLA4 mAb in a mouse melanoma model. Am J Cancer Res (2014) 4(2):172-81.
101. Wennerberg E, Kawashima N, Demaria S. Adenosine regulates radiation therapy-induced anti-tumor immunity. J Immunother Cancer (2015) 3(Suppl 2):378. doi:10.1186/2051-1426-3-S2-P378
102. Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol (2006) 24:99-146. doi:10.1146/annurev.immunol.24.021605.090737
103. Letterio JJ, Roberts AB. Regulation of immune responses by TGF-beta. Annu Rev Immunol (1998) 16:137-61. doi:10.1146/annurev.immunol.16.1.137
104. Gros MJ, Naquet P, Guinamard RR. Cell intrinsic TGF-beta 1 regulation of B cells. J Immunol (2008) 180(12):8153-8. doi:10.4049/jimmunol.180.12.8153
105. Li MO, Wan YY, Flavell RA. T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1-and Th17-cell differentiation. Immunity (2007) 26(5):579-91. doi:10.1016/j.immuni.2007.03.014
106. Rubtsov YP, Rudensky AY. TGFbeta signalling in control of T-cell-mediated self-reactivity. Nat Rev Immunol (2007) 7(6):443-53. doi:10.1038/nri2095
107. Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature (1992) 359(6397):693-9. doi:10.1038/359693a0
108. Yamagiwa S, Gray JD, Hashimoto S, Horwitz DA. A role for TGF-beta in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood. J Immunol (2001) 166(12):7282-9. doi:10.4049/jimmunol.166.12.7282
109. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, et al. Conversion of peripheral CD4+CD25-naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med (2003) 198(12):1875-86. doi:10.1084/jem.20030152
110. Thomas DA, Massague J. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell (2005) 8(5):369-80. doi:10.1016/j.ccr.2005.10.012
111. Regateiro FS, Howie D, Nolan KF, Agorogiannis EI, Greaves DR, Cobbold SP, et al. Generation of anti-inflammatory adenosine by leukocytes is regulated by TGF-beta. Eur J Immunol (2011) 41(10):2955-65. doi:10.1002/eji.201141512
112. Chalmin F, Mignot G, Bruchard M, Chevriaux A, Végran F, Hichami A, et al. Stat3 and Gfi-1 transcription factors control Th17 cell immunosuppressive activity via the regulation of ectonucleotidase expression. Immunity (2012) 36(3):362-73. doi:10.1016/j.immuni.2011.12.019
113. 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(3):183-94. doi:10.1016/j.ccr.2009.06.017
114. Tanaka H, Shinto O, Yashiro M, Yamazoe S, Iwauchi T, Muguruma K, et al. Transforming growth factor beta signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity. Oncol Rep (2010) 24(6):1637-43. doi:10.3892/or_00001028
115. Gratchev A. TGF-beta signalling in tumour associated macrophages. Immunobiology (2017) 222(1):75-81. doi:10.1016/j.imbio.2015.11.016
116. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol (2002) 23(11):549-55. doi:10.1016/S1471-4906(02)02302-5
117. Shaul ME, Levy L, Sun J, Mishalian I, Singhal S, Kapoor V, et al. Tumor-associated neutrophils display a distinct N1 profile following TGFbeta modulation: a transcriptomics analysis of pro-vs. antitumor TANs. Oncoimmunology (2016) 5(11):e1232221. doi:10.1080/2162402X.2016.1232221
118. Barcellos-Hoff MH, Derynck R, Tsang ML, Weatherbee JA. Transforming growth factor-beta activation in irradiated murine mammary gland. J Clin Invest (1994) 93(2):892-9. doi:10.1172/JCI117045
119. Jobling MF, Mott JD, Finnegan MT, Jurukovski V, Erickson AC, Walian PJ, et al. Isoform-specific activation of latent transforming growth factor beta (LTGF-beta) by reactive oxygen species. Radiat Res (2006) 166(6):839-48. doi:10.1667/RR0695.1
120. Vanpouille-Box C, Diamond JM, Pilones KA, Zavadil J, Babb JS, Formenti SC, et al. TGFbeta is a master regulator of radiation therapy-induced antitumor immunity. Cancer Res (2015) 75(11):2232-42. doi:10.1158/0008-5472.CAN-14-3511
121. Dovedi SJ, Adlard AL, Lipowska-Bhalla G, McKenna C, Jones S, Cheadle EJ, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res (2014) 74(19):5458-68. doi:10.1158/0008-5472.CAN-14-1258
122. Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med (2012) 4(127):127ra37. doi:10.1126/scitranslmed.3003689
123. Ruf M, Moch H, Schraml P. PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma. Int J Cancer (2016) 139(2):396-403. doi:10.1002/ijc.30077
124. Kang J, Demaria S, Formenti S. Current clinical trials testing the combination of immunotherapy with radiotherapy. J Immunother Cancer (2016) 4:51. doi:10.1186/s40425-016-0156-7
125. Pilones KA, Vanpouille-Box C, Demaria S. Combination of radiotherapy and immune checkpoint inhibitors. Semin Radiat Oncol (2015) 25(1):28-33. doi:10.1016/j.semradonc.2014.07.004
126. Vacchelli E, Bloy N, Aranda F, Buqué A, Cremer I, Demaria S, et al. Trial watch: immunotherapy plus radiation therapy for oncological indications. Oncoimmunology (2016) 5(9):e1214790. doi:10.1080/2162402X.2016.1214790
127. Hodi FS, Lawrence D, Lezcano C, Wu X, Zhou J, Sasada T, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res (2014) 2(7):632-42. doi:10.1158/2326-6066.CIR-14-0053
128. Wu X, Giobbie-Hurder A, Liao X, Lawrence D, McDermott D, Zhou J, et al. VEGF neutralization plus CTLA-4 blockade alters soluble and cellular factors associated with enhancing lymphocyte infiltration and humoral recognition in melanoma. Cancer Immunol Res (2016) 4(10):858-68. doi:10.1158/2326-6066.CIR-16-0084
129. Melsens E, Verberckmoes B, Rosseel N, Vanhove C, Descamps B, Pattyn P, et al. The VEGFR inhibitor cediranib improves the efficacy of fractionated radiotherapy in a colorectal cancer xenograft model. Eur Surg Res (2016) 58(3-4):95-108. doi:10.1159/000452741
130. Rodon J, Carducci MA, Sepulveda-Sánchez JM, Azaro A, Calvo E, Seoane J, et al. First-in-human dose study of the novel transforming growth factor-beta receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma. Clin Cancer Res (2015) 21(3):553-60. doi:10.1158/1078-0432.CCR-14-1380
131. Kovacs RJ, Maldonado G, Azaro A, Fernández MS, Romero FL, Sepulveda-Sánchez JM, et al. Cardiac safety of TGF-beta receptor I kinase inhibitor LY2157299 monohydrate in cancer patients in a first-in-human dose study. Cardiovasc Toxicol (2015) 15(4):309-23. doi:10.1007/s12012-014-9297-4
132. Morris JC, Tan AR, Olencki TE, Shapiro GI, Dezube BJ, Reiss M, et al. Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-beta (TGFbeta) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma. PLoS One (2014) 9(3):e90353. doi:10.1371/journal.pone.0090353
133. Allavena P, Sica A, Solinas G, Porta C, Mantovani A. The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol (2008) 66(1):1-9. doi:10.1016/j.critrevonc.2007.07.004
134. Tap WD, Wainberg ZA, Anthony SP, Ibrahim PN, Zhang C, Healey JH, et al. Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor. N Engl J Med (2015) 373(5):428-37. doi:10.1056/NEJMoa1411366
135. Bonnefoy N, Bastid J, Alberici G, Bensussan A, Eliaou JF. CD39: a complementary target to immune checkpoints to counteract tumor-mediated immunosuppression. Oncoimmunology (2015) 4(5):e1003015. doi:10.1080/2162402X.2014.1003015