Myeloid Cells as Targets for Therapy in Solid Tumors

Cancer Journal (United States)

Volumn 21, Issue 4, 2015, Pages 343-350

  Cotechini, Tiziana ^a   Medler, Terry R ^a   Coussens, Lisa M ^a  

^a OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

Author keywords

B cell; CD8 + T cell; chemotherapy; dendritic cell; eosinophil; immunotherapy; lymphocyte; macrophage; myeloid; neutrophil; tumor microenvironment

Indexed keywords

IPILIMUMAB; NIVOLUMAB; PEMBROLIZUMAB;

ANTIGEN ANTIBODY COMPLEX; B LYMPHOCYTE; BONE MARROW CELL; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; DENDRITIC CELL; EOSINOPHIL; GRANULOCYTE; HUMAN; MACROPHAGE; MONOCYTE; NEUTROPHIL; NONHUMAN; POLARIZATION; PRIORITY JOURNAL; REVIEW; SOLID TUMOR; TH1 CELL; TREATMENT RESPONSE; TUMOR GROWTH; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT; TUMOR REGRESSION; CYTOTOXIC T LYMPHOCYTE; IMMUNOLOGY; NEOPLASMS;

B-LYMPHOCYTES; DENDRITIC CELLS; EOSINOPHILS; GRANULOCYTES; HUMANS; MACROPHAGES; MONOCYTES; MYELOID CELLS; NEOPLASMS; NEUTROPHILS; T-LYMPHOCYTES, CYTOTOXIC; TUMOR MICROENVIRONMENT;

EID: 84938597972     PISSN: 15289117     EISSN: 1540336X     Source Type: Journal    
DOI: 10.1097/PPO.0000000000000132     Document Type: Review

References (127)

1. Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309-322.
2. Hanahan D,Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674.
3. Coussens LM, Zitvogel L, Palucka AK. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science. 2013;339:286-291.
4. Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol. 2002;196:254-265.
5. Ruffell B, Au A, Rugo HS, et al. Leukocyte composition of human breast cancer. Proc Natl Acad Sci U S A. 2012;109:2796-2801.
6. Tlsty TD, Coussens LM. Tumor stroma and regulation of cancer developement. Annu Rev Pathol. 2006;1:119-150.
7. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14:1014-1022.
8. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41:49-61.
9. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496:445-455.
10. Ruffell B, Affara NI, Coussens LM.Differentialmacrophage programming in the tumor microenvironment. Trends Immunol. 2012;33:119-126.
11. Mills CD, Kincaid K, Alt JM, et al. M-1/M-2 macrophages and the TH1/ TH2 paradigm. J Immunol. 2000;164:6166-6173.
12. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39-51.
13. Murray PJ, Allen JE, Biswas SK, et al.Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41:14-20.
14. Wu TC, Xu K, Banchereau R, et al. Reprogramming tumor-infiltrating dendritic cells for CD103+ CD8+ mucosal T-cell differentiation and breast cancer rejection. Cancer Immunol Res. 2014;2:487-500.
15. Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell. 2009;16:183-194.
16. Guilliams M, Ginhoux F, Jakubzick C, et al. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat Rev Immunol. 2014;14:571-578.
17. Palucka K, Ueno H, Fay J, et al. Dendritic cells and immunity against cancer. J Intern Med. 2011;269:64-73.
18. Ma Y, Shurin GV, Peiyuan Z, et al. Dendritic cells in the cancer microenvironment. J Cancer. 2013;4:36-44.
19. Broz ML, Binnewies M, Boldajipour B, et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell. 2014;26:638-652.
20. DeNardo DG,Andreu P, Coussens LM. Interactions between lymphocytes and myeloid cells regulate pro-versus anti-tumor immunity. Cancer Metastasis Rev. 2010;29:309-316.
21. Komohara Y, Jinushi M, Takeya M. Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci. 2014;105:1-8.
22. Kim DW, Min HS, Lee KH, et al. High tumour islet macrophage infiltration correlates with improved patient survival but not with EGFR mutations, gene copy number or protein expression in resected non-small cell lung cancer. Br J Cancer. 2008;98:1118-1124.
23. Martin DN, Boersma BJ, Yi M, et al. Differences in the tumor microenvironment between African-American and European-American breast cancer patients. PLoS One. 2009;4:e4531.
24. DeNardo DG, Brennan DJ, Rexhepaj E, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 2011;1:54-67.
25. CampbellMJ, Tonlaar NY, Garwood ER, et al. Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome. Breast Cancer Res Treat. 2011;128:703-711.
26. Chihara T, Suzu S, Hassan R, et al. IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation. Cell Death Differ. 2010;17:1917-1927.
27. Qian BZ, Li J, Zhang H, et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature. 2011;475:222-225.
28. Soria G, Ben-Baruch A. The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer Lett. 2008;267:271-285.
29. Beck AH, Espinosa I, Edris B, et al. The macrophage colony-stimulating factor 1 response signature in breast carcinoma. Clin Cancer Res. 2009; 15:778-787.
30. Aharinejad S, SalamaM, Paulus P, et al. Elevated CSF1 serum concentration predicts poor overall survival in women with early breast cancer. Endocr Relat Cancer. 2013;20:777-783.
31. Lin EY, Nguyen AV, Russell RG, et al. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med. 2001;193:727-740.
32. Ruffell B, Chang-Strachan D, Chan V, 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: 623-637.
33. Shiao SL, Ruffell B, DeNardo DG, et al. TH2-polarized CD4+ T cells and macrophages limit efficacy of radiotherapy. Cancer Immunol Res. 2015;3: 518-525.
34. Strachan DC, Ruffell B, Oei Y, 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.
35. Kretschmann KL, Eyob H, Buys SS, et al. The macrophage stimulating protein/RON pathway as a potential therapeutic target to impede multiple mechanisms involved in breast cancer progression. Curr Drug Targets. 2010;11:1157-1168.
36. Eyob H, Ekiz HA,Welm AL. RON promotes the metastatic spread of breast carcinomas by subverting antitumor immune responses. Oncoimmunology. 2013;2:e25670.
37. Eyob H, Ekiz HA, Derose YS, et al. Inhibition of RON kinase blocks conversion of micrometastases to overt metastases by boosting antitumor immunity. Cancer Discov. 2013;3:751-760.
38. Pyonteck SM, Akkari L, Schuhmacher AJ, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013; 19:1264-1272.
39. Xu J, Escamilla J, Mok S, et al. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res. 2013;73:2782-2794.
40. Amit M, Gil Z. Macrophages increase the resistance of pancreatic adenocarcinoma cells to gemcitabine by upregulating cytidine deaminase. Oncoimmunology. 2013;2:e27231.
41. Mitchem JB, Brennan DJ, Knolhoff BL, et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 2013;73: 1128-1141.
42. Pyonteck SM, Gadea BB,WangHW, et al. Deficiency of the macrophage growth factor CSF-1 disrupts pancreatic neuroendocrine tumor development. Oncogene. 2012;31:1459-1467.
43. Zhu Y, Knolhoff BL, Meyer MA, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014;74:5057-5069.
44. Mok S, Koya RC, Tsui C, et al. Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy. Cancer Res. 2014;74:153-161.
45. Ries CH, Cannarile MA, Hoves S, et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell. 2014;25:846-859.
46. Bonapace L, Coissieux MM, Wyckoff J, et al. Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature. 2014;515:130-133.
47. Sugimura K, Miyata H, Tanaka K, et al. High infiltration of tumorassociated macrophages is associated with a poor response to chemotherapy and poor prognosis of patients undergoing neoadjuvant chemotherapy for esophageal cancer. J Surg Oncol. 2015;111:752-759.
48. Angell H, Galon J. From the immune contexture to the Immunoscore: the role of prognostic and predictive immune markers in cancer. Curr Opin Immunol. 2013;25:261-267.
49. Galon J, Pages F, Marincola FM, et al. Cancer classification using the Immunoscore: a worldwide task force. J TranslMed. 2012;10:205.
50. FridmanWH, Pages F, Sautes-Fridman C, et al. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12: 298-306.
51. Lepique AP, Daghastanli KR, Cuccovia IM, et al. HPV16 tumor associated macrophages suppress antitumor T cell responses. Clin Cancer Res. 2009;15:4391-4400.
52. Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer. 2012;12:265-277.
53. VicariAP, Chiodoni C,Vaure C, et al. Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and antiinterleukin 10 receptor antibody. J Exp Med. 2002;196:541-549.
54. Palucka K, Coussens LM, O'Shaughnessy J. Dendritic cells, inflammation, and breast cancer. Cancer J. 2013;19:511-516.
55. Le Floc'h A, Jalil A, Vergnon I, et al. Alpha E beta 7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis. J ExpMed. 2007;204:559-570.
56. Aspord C, Pedroza-Gonzalez A, GallegosM, et al. Breast cancer instructs dendritic cells to prime interleukin 13-secreting CD4+ T cells that facilitate tumor development. J ExpMed. 2007;204:1037-1047.
57. Azab B, Bhatt VR, Phookan J, et al. Usefulness of the neutrophilto-lymphocyte ratio in predicting short-and long-term mortality in breast cancer patients. Ann Surg Oncol. 2012;19:217-224.
58. Noh H, Eomm M, Han A. Usefulness of pretreatment neutrophil to lymphocyte ratio in predicting disease-specific survival in breast cancer patients. J Breast Cancer. 2013;16:55-59.
59. Trellakis S, Bruderek K, Dumitru CA, et al. Polymorphonuclear granulocytes in human head and neck cancer: enhanced inflammatory activity, modulation by cancer cells and expansion in advanced disease. Int J Cancer. 2011;129:2183-2193.
60. Fridlender ZG, Albelda SM. Tumor-associated neutrophils: friend or foe? Carcinogenesis. 2012;33:949-955.
61. Abi Abdallah DS, Egan CE, Butcher BA, et al.Mouse neutrophils are professional antigen-presenting cells programmed to instruct TH1 and TH17 T-cell differentiation. Int Immunol. 2011;23:317-326.
62. Sippel TR, White J, Nag K, et al. Neutrophil degranulation and immunosuppression in patients with GBM: restoration of cellular immune function by targeting arginase I. Clin Cancer Res. 2011;17:6992-7002.
63. Coffelt SB, Kersten K, Doornebal CW, et al. IL-17-producing gammadelta T cells and neutrophils conspire to promote breast cancer metastasis. Nature. 2015;522:345-348.
64. Condamine T, Ramachandran I, Youn JI, et al. Regulation of tumor metastasis by myeloid-derived suppressor cells. Annu Rev Med. 2015;66:97-110.
65. Davis BP, RothenbergME. Eosinophils and cancer. Cancer Immunol Res. 2014;2:1-8.
66. Pretlow TP, Keith EF, Cryar AK, et al. Eosinophil infiltration of human colonic carcinomas as a prognostic indicator. Cancer Res. 1983;43: 2997-3000.
67. Flamm J. Tumor-associated tissue inflammatory reaction and eosinophilia in primary superficial bladder cancer. Urology. 1992;40:180-185.
68. Luna-More S, Florez P, Ayala A, et al. Neutral and acid mucins and eosinophil and argyrophil crystalloids in carcinoma and atypical adenomatous hyperplasia of the prostate. Pathol Res Pract. 1997;193:291-298.
69. vonWasielewski R, Seth S, Franklin J, et al. Tissue eosinophilia correlates strongly with poor prognosis in nodular sclerosing Hodgkin's disease, allowing for known prognostic factors. Blood. 2000;95:1207-1213.
70. van Driel WJ, Hogendoorn PC, Jansen FW, et al. Tumor-associated eosinophilic infiltrate of cervical cancer is indicative for a less effective immune response. Hum Pathol. 1996;27:904-911.
71. Horiuchi K, Mishima K, Ohsawa M, et al. Prognostic factors for welldifferentiated squamous cell carcinoma in the oral cavity with emphasis on immunohistochemical evaluation. J Surg Oncol. 1993;53:92-96.
72. Liu LY, Bates ME, Jarjour NN, et al. Generation of TH1 and TH2 chemokines by human eosinophils: evidence for a critical role of TNFalpha. J Immunol. 2007;179:4840-4848.
73. Carretero R, Sektioglu IM, Garbi N, et al. Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8(+) T cells. Nat Immunol. 2015;16:609-617.
74. Huland E, Huland H. Tumor-associated eosinophilia in interleukin-2-treated patients: evidence of toxic eosinophil degranulation on bladder cancer cells. J Cancer Res Clin Oncol. 1992;118:463-467.
75. Gatault S, Legrand F, Delbeke M, et al. Involvement of eosinophils in the anti-tumor response. Cancer Immunol Immunother. 2012;61:1527-1534.
76. Zhou L, ChongMM, Littman DR. Plasticity of CD4+ T cell lineage differentiation. Immunity. 2009;30:646-655.
77. Nishimura T, Iwakabe K, Sekimoto M, et al. Distinct role of antigenspecific T helper type 1 (TH1) and TH2 cells in tumor eradication in vivo. J ExpMed. 1999;190:617-627.
78. Bell D, Chomarat P, Broyles D, et al. In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J ExpMed. 1999;190:1417-1426.
79. DeNardo DG, Barreto JB, Andreu P, et al. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell. 2009;16:91-102.
80. Gocheva V, Wang HW, Gadea BB, et al. IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev. 2010;24:241-255.
81. Shree T, Olson OC, Elie BT, et al. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev. 2011;25: 2465-2479.
82. TokuraY, SeoN, Tomida M, et al.Augmentation ofmonocyte interleukin-8 production by psoralen/UVA-treated CD4+ T cells. Exp Dermatol. 2002; 11:564-572.
83. Gesser B, Lund M, Lohse N, et al. IL-8 induces T cell chemotaxis, suppresses IL-4, and up-regulates IL-8 production by CD4+ T cells. J Leukoc Biol. 1996;59:407-411.
84. Wittmann M, Alter M, Stunkel T, et al. Cell-to-cell contact between activated CD4+ T lymphocytes and unprimed monocytes interferes with a TH1 response. J Allergy Clin Immunol. 2004;114:965-973.
85. Gunderson AJ, Coussens LM. B cells and their mediators as targets for therapy in solid tumors. Exp Cell Res. 2013;319:1644-1649.
86. Tan TT, Coussens LM. Humoral immunity, inflammation and cancer. Curr Opin Immunol. 2007;19:209-216.
87. Monach PA, Schreiber H, Rowley DA. CD4+ and B lymphocytes in transplantation immunity. II. Augmented rejection of tumor allografts by mice lacking B cells. Transplantation. 1993;55:1356-1361.
88. Barbera-Guillem E, Nelson MB, Barr B, et al. B lymphocyte pathology in human colorectal cancer. Experimental and clinical therapeutic effects of partial B cell depletion. Cancer Immunol Immunother. 2000;48:541-549.
89. de Visser KE, Korets LV, Coussens LM. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell. 2005;7:411-423.
90. Schioppa T, Moore R, Thompson RG, et al. B regulatory cells and the tumor-promoting actions of TNF-alpha during squamous carcinogenesis. Proc Natl Acad Sci U S A. 2011;108:10662-10667.
91. Andreu P, Johansson M, Affara NI, et al. FcRgamma activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell. 2010; 17:121-134.
92. Wong SC, Puaux AL, Chittezhath M, et al. Macrophage polarization to a unique phenotype driven by B cells. Eur J Immunol. 2010;40:2296-2307.
93. Ammirante M, Luo JL, Grivennikov S, et al. B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature. 2010;464:302-305.
94. Woo JR, Liss MA, Muldong MT, et al. Tumor infiltrating B-cells are increased in prostate cancer tissue. J TranslMed. 2014;12:30.
95. Shalapour S, Font-Burgada J, Di Caro G, et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature. 2015;521:94-98.
96. Affara NI, Ruffell B, Medler TR, et al. B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas. Cancer Cell. 2014;25:809-821.
97. Inoue S, Leitner WW, Golding B, et al. Inhibitory effects of B cells on antitumor immunity. Cancer Res. 2006;66:7741-7747.
98. Bradley LM, Harbertson J, Biederman E, et al. Availability of antigenpresenting cells can determine the extent of CD4 effector expansion and priming for secretion of TH2 cytokines in vivo. Eur J Immunol. 2002; 32:2338-2346.
99. Shah S, Divekar AA, Hilchey SP, et al. Increased rejection of primary tumors in mice lacking B cells: inhibition of anti-tumor CTL and TH1 cytokine responses by B cells. Int J Cancer. 2005;117:574-586.
100. Honigberg LA, Smith AM, SirisawadM, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010;107:13075-13080.
101. Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/ refractory B-cell malignancies. J ClinOncol. 2013;31:88-94.
102. Byrd JC, Furman RR, Coutre SE, et al. Targeting Btk with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32-42.
103. Byrd JC, O'Brien S, James DF. Ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:1278-1279.
104. Wang ML, Rule S,Martin P, et al. Targeting Btk with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507-516.
105. Masso-Valles D, Jauset T, Serrano E, et al. Ibrutinib exerts potent antifibrotic and antitumor activities in mouse models of pancreatic adenocarcinoma. Cancer Res. 2015;75:1675-1681.
106. Soucek L, Buggy JJ, Kortlever R, et al. Modeling pharmacological inhibition of mast cell degranulation as a therapy for insulinoma. Neoplasia. 2011;13:1093-1100.
107. Sagiv-Barfi I, Kohrt HE, Czerwinski DK, et al. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both Btk and ITK. Proc Natl Acad Sci U S A. 2015;112:E966-E972.
108. Ni Gabhann J, Hams E, Smith S, et al. Btk regulates macrophage polarization in response to lipopolysaccharide. PLoS One. 2014;9:e85834.
109. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl JMed. 2014;370:997-1007.
110. GopalAK, Kahl BS, deVos S, et al. PI3K inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008-1018.
111. Chantry D, Vojtek A, Kashishian A, et al. P110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes.JBiolChem. 1997;272:19236-19241.
112. Ali K, Soond DR, Piñeiro R, et al. Inactivation of PI(3)K p110 breaks regulatory T-cell-mediated immune tolerance to cancer. Nature. 2014; 510:407-411.
113. Schmid MC, Franco I, Kang SW, et al. PI3-kinase promotes Rap1amediated activation of myeloid cell integrin 41, leading to tumor inflammation and growth. PLoS One. 2013;8:e60226.
114. Kroemer G, Galluzzi L, Kepp O, et al. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51-72.
115. MaY, Conforti R,Aymeric L, et al.Howto improve the immunogenicity of chemotherapy and radiotherapy. Cancer Metastasis Rev. 2011;30:71-82.
116. Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science. 2002;295:2387-2392.
117. Cook KM, Figg WD. Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin. 2010;60:222-243.
118. Kerbel R. Anti-angiogenesis in cancer; met and unmet goals-an interview with Robert Kerbel by Francesco Bertolini. Int J Dev Biol. 2011; 55:395-398.
119. Cao Y, Arbiser J, D'Amato RJ, et al. Forty-year journey of angiogenesis translational research. Sci Transl Med. 2011;3:114rv3.
120. Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell. 2015;27:462-472.
121. Wolchok JD, Hodi FS, Weber JS, et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci. 2013;1291:1-13.
122. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-133.
123. Robert C, RibasA,Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384:1109-1117.
124. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) inmelanoma.NEngl JMed. 2013;369:134-144.
125. PostowMA, Chesney J, PavlickAC, et al.Nivolumab and ipilimumabversus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006-2017.
126. Kirk PS, Koreckij T, Nguyen HM, et al. Inhibition of CCL2 signaling in combination with docetaxel treatment has profound inhibitory effects on prostate cancer growth in bone. Int J Mol Sci. 2013;14(5):10483-96.
127. Schmid MC, Avraamides CJ, Dippold HC, et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kgamma, a single convergent point promoting tumor inflammation and progression. Cancer Cell. 2011;19(6):715-27.