Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy

Nature Reviews Immunology

Volumn 17, Issue 9, 2017, Pages 559-572

  Nagarsheth, Nisha ^a,b   Wicha, Max S ^a,b   Zou, Weiping ^a,b  

^a UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^b UNIVERSITY OF MICHIGAN   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CCX 872; CHEMOKINE; CHEMOKINE RECEPTOR; CHEMOKINE RECEPTOR CCR2 ANTAGONIST; CHEMOKINE RECEPTOR CXCR4 ANTAGONIST; CXCL14 CHEMOKINE; CXCL9 CHEMOKINE; DECITABINE; DURVALUMAB; GAMMA INTERFERON INDUCIBLE PROTEIN 10; GSK 126; INTERLEUKIN 8; LY 2510924; MACROPHAGE INFLAMMATORY PROTEIN 1ALPHA; MARAVIROC; MONOCYTE CHEMOTACTIC PROTEIN 1; PLERIXAFOR; PROTEIN INHIBITOR; RANTES; REPARIXIN; STROMAL CELL DERIVED FACTOR 1; UNCLASSIFIED DRUG;

CANCER GROWTH; CANCER IMMUNOTHERAPY; CARCINOGENESIS; CELL SUBPOPULATION; CELLULAR DISTRIBUTION; DRUG TARGETING; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNE SYSTEM; IMMUNOCOMPETENT CELL; NONHUMAN; OVARY CANCER; PANCREAS CANCER; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; TREATMENT OUTCOME; TUMOR CELL; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT; IMMUNOLOGY; IMMUNOTHERAPY; NEOPLASMS;

CHEMOKINES; HUMANS; IMMUNOTHERAPY; NEOPLASMS; RECEPTORS, CHEMOKINE; TUMOR MICROENVIRONMENT;

EID: 85028431759     PISSN: 14741733     EISSN: 14741741     Source Type: Journal    
DOI: 10.1038/nri.2017.49     Document Type: Review

References (216)

1. Rot, A., & von Andrian, U. H. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu. Rev. Immunol. 22, 891-928 (2004
2. Griffith, J. W., Sokol, C. L., & Luster, A. D. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu. Rev. Immunol. 32, 659-702 (2014
3. Balkwill, F. Cancer and the chemokine network. Nat. Rev. Cancer 4, 540-550 (2004
4. Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat. Rev. Cancer 5, 263-274 (2005
5. Zou, W. Regulatory T cells, tumour immunity and immunotherapy. Nat. Rev. Immunol. 6, 295-307 (2006
6. Wei, S., Kryczek, I., & Zou, W. Regulatory T cell compartmentalization and trafficking. Blood 108, 426-431 (2006
7. Zou, W., & Chen, L. Inhibitory B7 family molecules in the tumour microenvironment. Nat. Rev. Immunol. 8, 467-477 (2008
8. Zou, W., & Restifo, N. P. TH17 cells in tumour immunity and immunotherapy. Nat. Rev. Immunol. 10, 248-256 (2010
9. Crespo, J., Sun, H., Welling, T. H., Tian, Z., & Zou, W. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr. Opin. Immunol. 25, 214-221 (2013
10. Zou, W., Wolchok, J. D., & Chen, L. PD L1 (B7 H1) and PD 1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci. Transl Med. 8, 328rv324 (2016
11. Topalian, S. L., Drake, C. G., & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450-461 (2015
12. Homey, B., Muller, A., & Zlotnik, A. Chemokines: agents for the immunotherapy of cancer? Nat. Rev. Immunol. 2, 175-184 (2002
13. Zhang, L., et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203-213 (2003
14. Pages, F., et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N. Engl. J. Med. 353, 2654-2666 (2005
15. Sato, E., et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc. Natl Acad. Sci. USA 102, 18538-18543 (2005
16. Galon, J., et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960-1964 (2006
17. Kryczek, I., et al. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 114, 1141-1149 (2009
18. Zhao, E., et al. Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat. Immunol. 17, 95-103 (2016
19. Wang, W., et al. Effector T cells abrogate stroma-mediated chemoresistance in ovarian cancer. Cell 165, 1092-1105 (2016
20. Acosta-Rodriguez, E. V., et al. Surface phenotype and antigenic specificity of human interleukin 17 producing T helper memory cells. Nat. Immunol. 8, 639-646 (2007
21. Kryczek, I., et al. Induction of IL 17+ T cell trafficking and development by IFN-κ: mechanism and pathological relevance in psoriasis. J. Immunol. 181, 4733-4741 (2008
22. Kryczek, I., et al. Human TH17 cells are long-lived effector memory cells. Sci. Transl Med. 3, 104ra100 (2011
23. Muranski, P., et al. Tumor-specific Th17 polarized cells eradicate large established melanoma. Blood 112, 362-373 (2008
24. Martin-Orozco, N., et al. T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity 31, 787-798 (2009
25. Zou, W., et al. Stromal-derived factor 1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat. Med. 7, 1339-1346 (2001
26. Kryczek, I., et al. CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. Cancer Res. 65, 465-472 (2005
27. Bell, D., et al. In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J. Exp. Med. 190, 1417-1426 (1999
28. Wei, S., Zhao, E., Kryczek, I., & Zou, W. Th17 cells have stem cell-like features and promote long-term tumor immunity. Oncoimmunology 1, 516-519 (2012
29. Kryczek, I., Wei, S., Szeliga, W., Vatan, L., & Zou, W. Endogenous IL 17 contributes to reduced tumor growth and metastasis. Blood 114, 357-359 (2009
30. Kryczek, I., et al. IL 22+CD4+ T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L. Immunity 40, 772-784 (2014
31. Huang, Y. H., Cao, Y. F., Jiang, Z. Y., Zhang, S., & Gao, F. Th22 cell accumulation is associated with colorectal cancer development. World J. Gastroenterol. 21, 4216-4224 (2015
32. Zhuang, Y., et al. Increased intratumoral IL 22 producing CD4+ T cells and Th22 cells correlate with gastric cancer progression and predict poor patient survival. Cancer Immunol. Immunother. 61, 1965-1975 (2012
33. Kuang, D. M., et al. B7 H1 expressing antigen-presenting cells mediate polarization of protumorigenic Th22 subsets. J. Clin. Invest. 124, 4657-4667 (2014
34. Sun, D., et al. Th22 cells control colon tumorigenesis through STAT3 and Polycomb repression complex 2 signaling. Oncoimmunology 5, e1082704 (2016
35. Kirchberger, S., et al. Innate lymphoid cells sustain colon cancer through production of interleukin 22 in a mouse model. J. Exp. Med. 210, 917-931 (2013
36. Huber, S., et al. IL 22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491, 259-263 (2012
37. Perusina Lanfranca, M., Lin, Y., Fang, J., Zou, W., & Frankel, T. Biological and pathological activities of interleukin 22. J. Mol. Med. (Berl.) 94, 523-534 (2016
38. Curiel, T. J., et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942-949 (2004
39. Facciabene, A., et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475, 226-230 (2011
40. Zhao, E., et al. Bone marrow and the control of immunity. Cell. Mol. Immunol. 9, 11-19 (2012
41. Zou, L., et al. Bone marrow is a reservoir for CD4+CD25+ regulatory T cells that traffic through CXCL12/CXCR4 signals. Cancer Res. 64, 8451-8455 (2004
42. Zhao, E., et al. Regulatory T cells in the bone marrow microenvironment in patients with prostate cancer. Oncoimmunology 1, 152-161 (2012
43. Kryczek, I., et al. Inflammatory regulatory T cells in the microenvironments of ulcerative colitis and colon carcinoma. Oncoimmunology 5, e1105430 (2016
44. Kryczek, I., et al. IL 17+ regulatory T cells in the microenvironments of chronic inflammation and cancer. J. Immunol. 186, 4388-4395 (2011
45. Berzofsky, J. A., & Terabe, M. NKT cells in tumor immunity: opposing subsets define a new immunoregulatory axis. J. Immunol. 180, 3627-3635 (2008
46. Kim, C. H., Johnston, B., & Butcher, E. C. Trafficking machinery of NKT cells: shared and differential chemokine receptor expression among Va24+Vβ11+ NKT cell subsets with distinct cytokine-producing capacity. Blood 100, 11-16 (2002
47. Metelitsa, L. S., et al. Natural killer T cells infiltrate neuroblastomas expressing the chemokine CCL2. J. Exp. Med. 199, 1213-1221 (2004
48. Song, L., et al. Oncogene MYCN regulates localization of NKT cells to the site of disease in neuroblastoma. J. Clin. Invest. 117, 2702-2712 (2007
49. Nelson, B. H. CD20+ B cells: the other tumor-infiltrating lymphocytes. J. Immunol. 185, 4977-4982 (2010
50. Schmidt, M., et al. The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res. 68, 5405-5413 (2008
51. Milne, K., et al. Systematic analysis of immune infiltrates in high-grade serous ovarian cancer reveals CD20, FoxP3 and TIA 1 as positive prognostic factors. PLoS ONE 4, e6412 (2009
52. Nedergaard, B. S., Ladekarl, M., Nyengaard, J. R., & Nielsen, K. A comparative study of the cellular immune response in patients with stage IB cervical squamous cell carcinoma. Low numbers of several immune cell subtypes are strongly associated with relapse of disease within 5 years. Gynecol. Oncol. 108, 106-111 (2008
53. Germain, C., Gnjatic, S., & Dieu-Nosjean, M. C. Tertiary lymphoid structure-associated B cells are key players in anti-tumor immunity. Front. Immunol. 6, 67 (2015
54. Andreu, P., et al. FcR? activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17, 121-134 (2010
55. Yang, C., et al. B cells promote tumor progression via STAT3 regulated-angiogenesis. PLoS ONE 8, e64159 (2013
56. Affara, N. I., et al. B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas. Cancer Cell 25, 809-821 (2014
57. Mizoguchi, A., & Bhan, A. K. A case for regulatory B cells. J. Immunol. 176, 705-710 (2006
58. Banchereau, J., & Palucka, A. K. Dendritic cells as therapeutic vaccines against cancer. Nat. Rev. Immunol. 5, 296-306 (2005
59. Pedroza-Gonzalez, A., et al. Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation. J. Exp. Med. 208, 479-490 (2011
60. Aspord, C., et al. Breast cancer instructs dendritic cells to prime interleukin 13 secreting CD4+ T cells that facilitate tumor development. J. Exp. Med. 204, 1037-1047 (2007
61. Fushimi, T., Kojima, A., Moore, M. A., & Crystal, R. G. Macrophage inflammatory protein 3a transgene attracts dendritic cells to established murine tumors and suppresses tumor growth. J. Clin. Invest. 105, 1383-1393 (2000
62. Shurin, G. V., et al. Loss of new chemokine CXCL14 in tumor tissue is associated with low infiltration by dendritic cells (DC), while restoration of human CXCL14 expression in tumor cells causes attraction of DC both in vitro and in vivo. J. Immunol. 174, 5490-5498 (2005
63. Scotton, C. J., Wilson, J. L., Milliken, D., Stamp, G., & Balkwill, F. R. Epithelial cancer cell migration: a role for chemokine receptors? Cancer Res. 61, 4961-4965 (2001
64. Wei, S., et al. Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Res. 65, 5020-5026 (2005
65. Curiel, T. J., et al. Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer. Cancer Res. 64, 5535-5538 (2004
66. Qian, B. Z., et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222-225 (2011
67. Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer 4, 71-78 (2004
68. Kryczek, I., et al. B7 H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J. Exp. Med. 203, 871-881 (2006
69. Wu, K., Kryczek, I., Chen, L., Zou, W., & Welling, T. H. Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7 H1/programmed death 1 interactions. Cancer Res. 69, 8067-8075 (2009
70. Li, H., et al. Tim 3/galectin 9 signaling pathway mediates T cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology 56, 1342-1351 (2012
71. Kuang, D. M., et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD L1. J. Exp. Med. 206, 1327-1337 (2009
72. Denardo, D. G., et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54-67 (2011
73. Wan, S., et al. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 147, 1393-1404 (2014
74. Kitamura, T., et al. CCL2 induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J. Exp. Med. 212, 1043-1059 (2015
75. Luboshits, G., et al. Elevated expression of the CC chemokine regulated on activation, normal T cell expressed and secreted (RANTES) in advanced breast carcinoma. Cancer Res. 59, 4681-4687 (1999
76. Azenshtein, E., et al. The CC chemokine RANTES in breast carcinoma progression: regulation of expression and potential mechanisms of promalignant activity. Cancer Res. 62, 1093-1102 (2002
77. Edin, S., et al. The distribution of macrophages with a M1 or M2 phenotype in relation to prognosis and the molecular characteristics of colorectal cancer. PLoS ONE 7, e47045 (2012
78. Kuang, D. M., et al. Tumor-activated monocytes promote expansion of IL 17 producing CD8+ T cells in hepatocellular carcinoma patients. J. Immunol. 185, 1544-1549 (2010
79. Forssell, J., et al. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin. Cancer Res. 13, 1472-1479 (2007
80. Asano, K., et al. CD169 positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens. Immunity 34, 85-95 (2011
81. De Palma, M., & Lewis, C. E. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23, 277-286 (2013
82. Gabrilovich, D. I., & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162-174 (2009
83. Rodriguez, P. C., et al. Arginase I in myeloid suppressor cells is induced by COX 2 in lung carcinoma. J. Exp. Med. 202, 931-939 (2005
84. Huang, B., et al. Gr 1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T cell anergy in tumor-bearing host. Cancer Res. 66, 1123-1131 (2006
85. Marigo, I., et al. Tumor-induced tolerance and immune suppression depend on the C/EBPβ transcription factor. Immunity 32, 790-802 (2010
86. Cui, T. X., et al. Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2. Immunity 39, 611-621 (2013
87. Panni, R. Z., et al. Tumor-induced STAT3 activation in monocytic myeloid-derived suppressor cells enhances stemness and mesenchymal properties in human pancreatic cancer. Cancer Immunol. Immunother. 63, 513-528 (2014
88. Peng, D., et al. Myeloid-derived suppressor cells endow stem-like qualities to breast cancer cells through IL6/STAT3 and NO/NOTCH cross-talk signaling. Cancer Res. 76, 3156-3165 (2016
89. Pollard, J. W. Trophic macrophages in development and disease. Nat. Rev. Immunol. 9, 259-270 (2009
90. Yang, L., et al. Abrogation of TGFβ signaling in mammary carcinomas recruits Gr 1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13, 23-35 (2008
91. Waugh, D. J. J., & Wilson, C. The interleukin 8 pathway in cancer. Clin. Cancer Res. 14, 6735-6741 (2008
92. De Larco, J. E., Wuertz, B. R. K., & Furcht, L. T. The potential role of neutrophils in promoting the metastatic phenotype of tumors releasing interleukin 8. Clin. Cancer Res. 10, 4895-4900 (2004
93. Wolf, M. J., et al. Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway. Cancer Cell 22, 91-105 (2012
94. Goede, V., Brogelli, L., Ziche, M., & Augustin, H. G. Induction of inflammatory angiogenesis by monocyte chemoattractant protein 1. Int. J. Cancer 82, 765-770 (1999
95. Saji, H., et al. Significant correlation of monocyte chemoattractant protein 1 expression with neovascularization and progression of breast carcinoma. Cancer 92, 1085-1091 (2001
96. Bonapace, L., et al. Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature 515, 130-133 (2014
97. Robinson, S. C., Scott, K. A., & Balkwill, F. R. Chemokine stimulation of monocyte matrix metalloproteinase 9 requires endogenous TNF-a. Eur. J. Immunol. 32, 404-412 (2002
98. Stamenkovic, I. Matrix metalloproteinases in tumor invasion and metastasis. Semin. Cancer Biol. 10, 415-433 (2000
99. Fang, W. B., et al. CCL2/CCR2 chemokine signaling coordinates survival and motility of breast cancer cells through Smad3 protein-and p42/44 mitogen-activated protein kinase (MAPK)-dependent mechanisms. J. Biol. Chem. 287, 36593-36608 (2012
100. Tsuyada, A., et al. CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. Cancer Res. 72, 2768-2779 (2012
101. Long, H., et al. Autocrine CCL5 signaling promotes invasion and migration of CD133+ ovarian cancer stem-like cells via NF-κB-mediated MMP 9 upregulation. Stem Cells 30, 2309-2319 (2012
102. Zou, W., & Wicha, M. S. Chemokines and cellular plasticity of ovarian cancer stem cells. Oncoscience 2, 615-616 (2015
103. Long, H., et al. CD133+ ovarian cancer stem-like cells promote non-stem cancer cell metastasis via CCL5 induced epithelial-mesenchymal transition. Oncotarget 6, 5846-5859 (2015
104. Lu, H., et al. A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat. Cell Biol. 16, 1105-1117 (2014
105. Chen, J., et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell 19, 541-555 (2011
106. Wang, Q., et al. CCL18 from tumor-cells promotes epithelial ovarian cancer metastasis via mTOR signaling pathway. Mol. Carcinog. 55, 1688-1699 (2016
107. Lin, L., et al. CCL18 from tumor-associated macrophages promotes angiogenesis in breast cancer. Oncotarget 6, 34758-34773 (2015
108. Meng, F., et al. CCL18 promotes epithelial-mesenchymal transition, invasion and migration of pancreatic cancer cells in pancreatic ductal adenocarcinoma. Int. J. Oncol. 46, 1109-1120 (2015
109. Chen, G., et al. CC chemokine ligand 18 correlates with malignant progression of prostate cancer. Biomed Res. Int. 2014, 230183 (2014
110. Leung, S. Y., et al. Expression profiling identifies chemokine (C C motif) ligand 18 as an independent prognostic indicator in gastric cancer. Gastroenterology 127, 457-469 (2004
111. Gunther, C., et al. Up regulation of the chemokine CCL18 by macrophages is a potential immunomodulatory pathway in cutaneous T cell lymphoma. Am. J. Pathol. 179, 1434-1442 (2011
112. Vulcano, M., et al. Unique regulation of CCL18 production by maturing dendritic cells. J. Immunol. 170, 3843-3849 (2003
113. Schutyser, E., Richmond, A., & Van Damme, J. Involvement of CC chemokine ligand 18 (CCL18) in normal and pathological processes. J. Leukoc. Biol. 78, 14-26 (2005
114. Azzaoui, I., et al. CCL18 differentiates dendritic cells in tolerogenic cells able to prime regulatory T cells in healthy subjects. Blood 118, 3549-3558 (2011
115. Schraufstatter, I. U., Zhao, M., Khaldoyanidi, S. K., & Discipio, R. G. The chemokine CCL18 causes maturation of cultured monocytes to macrophages in the M2 spectrum. Immunology 135, 287-298 (2012
116. Sharma, P. K., et al. CCR9 mediates PI3K/AKT-dependent antiapoptotic signals in prostate cancer cells and inhibition of CCR9-CCL25 interaction enhances the cytotoxic effects of etoposide. Int. J. Cancer 127, 2020-2030 (2010
117. Johnson, E. L., et al. CCR9 interactions support ovarian cancer cell survival and resistance to cisplatin-induced apoptosis in a PI3K dependent and FAK-independent fashion. J. Ovarian Res. 3, 15 (2010
118. Singh, S., Singh, U. P., Stiles, J. K., Grizzle, W. E., & Lillard, J. W. Jr. Expression and functional role of CCR9 in prostate cancer cell migration and invasion. Clin. Cancer Res. 10, 8743-8750 (2004
119. Johnson, E. L., et al. CCL25-CCR9 interaction modulates ovarian cancer cell migration, metalloproteinase expression, and invasion. World J. Surg. Oncol. 8, 62 (2010
120. Gupta, P., et al. CCR9/CCL25 expression in non-small cell lung cancer correlates with aggressive disease and mediates key steps of metastasis. Oncotarget 5, 10170-10179 (2014
121. Tu, Z., et al. CCR9 in cancer: oncogenic role and therapeutic targeting. J. Hematol. Oncol. 9, 10 (2016
122. Johnson-Holiday, C., et al. CCL25 mediates migration, invasion and matrix metalloproteinase expression by breast cancer cells in a CCR9 dependent fashion. Int. J. Oncol. 38, 1279-1285 (2011
123. Amersi, F. F., et al. Activation of CCR9/CCL25 in cutaneous melanoma mediates preferential metastasis to the small intestine. Clin. Cancer Res. 14, 638-645 (2008
124. Letsch, A., et al. Functional CCR9 expression is associated with small intestinal metastasis. J. Invest. Dermatol. 122, 685-690 (2004
125. Nagakubo, D., et al. Expression of CCR9 in HTLV 1+ T cells and ATL cells expressing Tax. Int. J. Cancer 120, 1591-1597 (2007
126. Li, A. H., Dubey, S., Varney, M. L., Dave, B. J., & Singh, R. K. IL 8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J. Immunol. 170, 3369-3376 (2003
127. Gabellini, C., et al. Functional activity of CXCL8 receptors, CXCR1 and CXCR2, on human malignant melanoma progression. Eur. J. Cancer 45, 2618-2627 (2009
128. Acosta, J. C., et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006-1018 (2008
129. Maxwell, P. J., et al. HIF 1 and NF-κB-mediated upregulation of CXCR1 and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells. Oncogene 26, 7333-7345 (2007
130. Fernando, R. I., Castillo, M. D., Litzinger, M., Hamilton, D. H., & Palena, C. IL 8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells. Cancer Res. 71, 5296-5306 (2011
131. Ginestier, C., et al. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J. Clin. Invest. 120, 485-497 (2010
132. Hwang, W. L., et al. SNAIL regulates interleukin 8 expression, stem cell-like activity, and tumorigenicity of human colorectal carcinoma cells. Gastroenterology 141, 279-291.e5 (2011
133. Liu, Y. N., et al. IL 8 confers resistance to EGFR inhibitors by inducing stem cell properties in lung cancer. Oncotarget 6, 10415-10431 (2015
134. Visciano, C., et al. Mast cells induce epithelial-to mesenchymal transition and stem cell features in human thyroid cancer cells through an IL 8-Akt-Slug pathway. Oncogene 34, 5175-5186 (2015
135. Chen, L., et al. The IL 8/CXCR1 axis is associated with cancer stem cell-like properties and correlates with clinical prognosis in human pancreatic cancer cases. Sci. Rep. 4, 5911 (2014
136. Kryczek, I., Wei, S., Keller, E., Liu, R., & Zou, W. Stroma-derived factor (SDF 1/CXCL12) and human tumor pathogenesis. Am. J. Physiol. Cell Physiol. 292, C987-C995 (2007
137. Scotton, C. J., et al. Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Cancer Res. 62, 5930-5938 (2002
138. Muller, A., et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50-56 (2001
139. Murakami, T., et al. Expression of CXC chemokine receptor 4 enhances the pulmonary metastatic potential of murine B16 melanoma cells. Cancer Res. 62, 7328-7334 (2002
140. Helbig, G., et al. NF-κB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J. Biol. Chem. 278, 21631-21638 (2003
141. Zeelenberg, I. S., Ruuls-Van Stalle, L., & Roos, E. The chemokine receptor CXCR4 is required for outgrowth of colon carcinoma micrometastases. Cancer Res. 63, 3833-3839 (2003
142. Darash-Yahana, M., et al. Role of high expression levels of CXCR4 in tumor growth, vascularization, and metastasis. FASEB J. 18, 1240-1242 (2004
143. Kang, Y., et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537-549 (2003
144. Jung, M. J., et al. Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells. Oncogene 32, 209-221 (2013
145. Cioffi, M., et al. Identification of a distinct population of CD133+CXCR4+ cancer stem cells in ovarian cancer. Sci. Rep. 5, 10357 (2015
146. Zhang, S. S., et al. CD133+CXCR4+ colon cancer cells exhibit metastatic potential and predict poor prognosis of patients. BMC Med. 10, 85 (2012
147. Balabanian, K., et al. The chemokine SDF 1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J. Biol. Chem. 280, 35760-35766 (2005
148. Burns, J. M., et al. A novel chemokine receptor for SDF 1 and I TAC involved in cell survival, cell adhesion, and tumor development. J. Exp. Med. 203, 2201-2213 (2006
149. Rajagopal, S., et al.β-Arrestin-but not G protein-mediated signaling by the "decoy" receptor CXCR7. Proc. Natl Acad. Sci. USA 107, 628-632 (2010
150. Miao, Z., et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc. Natl Acad. Sci. USA 104, 15735-15740 (2007
151. Sun, X., et al. CXCL12 /CXCR4 /CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev. 29, 709-722 (2010
152. Levoye, A., Balabanian, K., Baleux, F., Bachelerie, F., & Lagane, B. CXCR7 heterodimerizes with CXCR4 and regulates CXCL12 mediated G protein signaling. Blood 113, 6085-6093 (2009
153. Wang, J., et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF 1 in prostate cancer. J. Biol. Chem. 283, 4283-4294 (2008
154. Singh, R. K., & Lokeshwar, B. L. The IL 8 regulated chemokine receptor CXCR7 stimulates EGFR signaling to promote prostate cancer growth. Cancer Res. 71, 3268-3277 (2011
155. Wente, M. N., et al. CXCL14 expression and potential function in pancreatic cancer. Cancer Lett. 259, 209-217 (2008
156. Schwarze, S. R., Luo, J., Isaacs, W. B., & Jarrard, D. F. Modulation of CXCL14 (BRAK) expression in prostate cancer. Prostate 64, 67-74 (2005
157. Hromas, R., et al. Cloning of BRAK, a novel divergent CXC chemokine preferentially expressed in normal versus malignant cells. Biochem. Biophys. Res. Commun. 255, 703-706 (1999
158. Gu, X. L., et al. Expression of CXCL14 and its anticancer role in breast cancer. Breast Cancer Res. Treat. 135, 725-735 (2012
159. Sleeman, M. A., et al. B cell-and monocyte-activating chemokine (BMAC), a novel non-ELR a-chemokine. Int. Immunol. 12, 677-689 (2000
160. Frederick, M. J., et al. In vivo expression of the novel CXC chemokine BRAK in normal and cancerous human tissue. Am. J. Pathol. 156, 1937-1950 (2000
161. Allinen, M., et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6, 17-32 (2004
162. Weinstein, E. J., et al. VCC 1, a novel chemokine, promotes tumor growth. Biochem. Biophys. Res. Commun. 350, 74-81 (2006
163. Matsui, A., et al. CXCL17 expression by tumor cells recruits CD11b+Gr1highF4/80-cells and promotes tumor progression. PLoS ONE 7, e44080 (2012
164. Lee, W. Y., Wang, C. J., Lin, T. Y., Hsiao, C. L., & Luo, C. W. CXCL17, an orphan chemokine, acts as a novel angiogenic and anti-inflammatory factor. Am. J. Physiol. Endocrinol. Metab. 304, E32-E40 (2013
165. Ohlsson, L., Hammarstrom, M. L., Lindmark, G., Hammarstrom, S., & Sitohy, B. Ectopic expression of the chemokine CXCL17 in colon cancer cells. Br. J. Cancer 114, 697-703 (2016
166. Sukkurwala, A. Q., et al. Immunogenic calreticulin exposure occurs through a phylogenetically conserved stress pathway involving the chemokine CXCL8. Cell Death Differ. 21, 59-68 (2014
167. Obeid, M., et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54-61 (2007
168. Carmeliet, P., & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249-257 (2000
169. Romagnani, P., et al. Cell cycle-dependent expression of CXC chemokine receptor 3 by endothelial cells mediates angiostatic activity. J. Clin. Invest. 107, 53-63 (2001
170. Strieter, R. M., Kunkel, S. L., Arenberg, D. A., Burdick, M. D., & Polverini, P. J. Interferon-κ-inducible protein 10 (Ip 10), a member of the C X C chemokine family, is an inhibitor of angiogenesis. Biochem. Biophys. Res. Commun. 210, 51-57 (1995
171. Angiolillo, A. L., et al. Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J. Exp. Med. 182, 155-162 (1995
172. Peng, D., et al. Epigenetic silencing of TH1 type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249-253 (2015
173. Nagarsheth, N., et al. PRC2 epigenetically silences Th1 type chemokines to suppress effector T cell trafficking in colon cancer. Cancer Res. 76, 275-282 (2016
174. Tessema, M., et al. Re expression of CXCL14, a common target for epigenetic silencing in lung cancer, induces tumor necrosis. Oncogene 29, 5159-5170 (2010
175. Spranger, S., Bao, R., & Gajewski, T. F. Melanoma-intrinsicβ-catenin signalling prevents anti-tumour immunity. Nature 523, 231-235 (2015
176. Ashburner, B. P., Westerheide, S. D., & Baldwin, A. S. Jr. The p65 (RelA) subunit of NF-κB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression. Mol. Cell. Biol. 21, 7065-7077 (2001
177. Mayo, M. W., et al. Ineffectiveness of histone deacetylase inhibitors to induce apoptosis involves the transcriptional activation of NF-κB through the Akt pathway. J. Biol. Chem. 278, 18980-18989 (2003
178. Ierano, C., et al. A point mutation (G574A) in the chemokine receptor CXCR4 detected in human cancer cells enhances migration. Cell Cycle 8, 1228-1237 (2009
179. Libura, J., et al. CXCR4-SDF 1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis, and adhesion. Blood 100, 2597-2606 (2002
180. Timp, W., & Feinberg, A. P. Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nat. Rev. Cancer 13, 497-510 (2013
181. Semenza, G. L. Targeting HIF 1 for cancer therapy. Nat. Rev. Cancer 3, 721-732 (2003
182. Hitchon, C., et al. Hypoxia-induced production of stromal cell-derived factor 1 (CXCL12) and vascular endothelial growth factor by synovial fibroblasts. Arthritis Rheum. 46, 2587-2597 (2002
183. Ceradini, D. J., et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF 1 induction of SDF 1. Nat. Med. 10, 858-864 (2004
184. Schioppa, T., et al. Regulation of the chemokine receptor CXCR4 by hypoxia. J. Exp. Med. 198, 1391-1402 (2003
185. Staller, P., et al. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 425, 307-311 (2003
186. Tarnowski, M., et al. Regulation of expression of stromal-derived factor 1 receptors: CXCR4 and CXCR7 in human rhabdomyosarcomas. Mol. Cancer Res. 8, 1-14 (2010
187. Mojsilovic-Petrovic, J., et al. Hypoxia-inducible factor 1 (HIF 1) is involved in the regulation of hypoxia-stimulated expression of monocyte chemoattractant protein 1 (MCP 1/CCL2) and MCP 1 (Ccl12) in astrocytes. J. Neuroinflammation 4, 12 (2007
188. Xu, L., Xie, K. P., Mukaida, N., Matsushima, K., & Fidler, I. J. Hypoxia-induced elevation in interleukin 8 expression by human ovarian carcinoma cells. Cancer Res. 59, 5822-5829 (1999
189. Vegran, F., Boidot, R., Michiels, C., Sonveaux, P., & Feron, O. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL 8 pathway that drives tumor angiogenesis. Cancer Res. 71, 2550-2560 (2011
190. Pelicano, H., et al. Mitochondrial dysfunction and reactive oxygen species imbalance promote breast cancer cell motility through a CXCL14 mediated mechanism. Cancer Res. 69, 2375-2383 (2009
191. Boudot, A., et al. Differential estrogen-regulation of CXCL12 chemokine receptors, CXCR4 and CXCR7, contributes to the growth effect of estrogens in breast cancer cells. PLoS ONE 6, e20898 (2011
192. Vetizou, M., et al. Anticancer immunotherapy by CTLA 4 blockade relies on the gut microbiota. Science 350, 1079-1084 (2015
193. Sivan, A., et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti PD L1 efficacy. Science 350, 1084-1089 (2015
194. Kostic, A. D., et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 14, 207-215 (2013
195. Maslowski, K. M., et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282-1286 (2009
196. Sokol, H., et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl Acad. Sci. USA 105, 16731-16736 (2008
197. Sommer, F., & Backhed, F. The gut microbiota - masters of host development and physiology. Nat. Rev. Microbiol. 11, 227-238 (2013
198. Wang, L., et al. Decitabine enhances lymphocyte migration and function and synergizes with CTLA 4 blockade in a murine ovarian cancer model. Cancer Immunol. Res. 3, 1030-1041 (2015
199. Tan, J., et al. Pharmacologic disruption of Polycomb-repressive complex 2 mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 21, 1050-1063 (2007
200. McCabe, M. T., et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2 activating mutations. Nature 492, 108-112 (2012
201. Li, H., et al. Immune regulation by low doses of the DNA methyltransferase inhibitor 5 azacitidine in common human epithelial cancers. Oncotarget 5, 587-598 (2014
202. Wrangle, J., et al. Alterations of immune response of non-small cell lung cancer with azacytidine. Oncotarget 4, 2067-2079 (2013
203. Woloszynska-Read, A., Mhawech-Fauceglia, P., Yu, J., Odunsi, K., & Karpf, A. R. Intertumor and intratumor NY ESO 1 expression heterogeneity is associated with promoter-specific and global DNA methylation status in ovarian cancer. Clin. Cancer Res. 14, 3283-3290 (2008
204. Donzella, G. A., et al. AMD3100, a small molecule inhibitor of HIV 1 entry via the CXCR4 co receptor. Nat. Med. 4, 72-77 (1998
205. Bertolini, F., et al. CXCR4 neutralization, a novel therapeutic approach for non-Hodgkin s lymphoma. Cancer Res. 62, 3106-3112 (2002
206. Rubin, J. B., et al. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc. Natl Acad. Sci. USA 100, 13513-13518 (2003
207. Liang, Z., et al. Silencing of CXCR4 blocks breast cancer metastasis. Cancer Res. 65, 967-971 (2005
208. Lapteva, N., Yang, A. G., Sanders, D. E., Strube, R. W., & Chen, S. Y. CXCR4 knockdown by small interfering RNA abrogates breast tumor growth in vivo. Cancer Gene Ther. 12, 84-89 (2005
209. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02737072 (2017
210. Bertini, R., et al. Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury. Proc. Natl Acad. Sci. USA 101, 11791-11796 (2004
211. Leitner, J. M., et al. Reparixin, a specific interleukin 8 inhibitor, has no effects on inflammation during endotoxemia. Int. J. Immunopathol. Pharmacol. 20, 25-36 (2007
212. Fridlender, Z. G., et al. CCL2 blockade augments cancer immunotherapy. Cancer Res. 70, 109-118 (2010
213. Zhu, Y., et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 74, 5057-5069 (2014
214. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01015560 (2015
215. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02345408 (2016
216. Matsui, A., Morikawa, S., & Ezaki, T. Possible roles of CXCL17 in angiogenesis during tumor progression. FASEB J. 29, 926.12 (2015