Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy

Key Points

  • Chemokines regulate the infiltration of different immune cell subsets into tumours and, as such, these molecules affect tumour immunity and influence therapeutic outcomes in patients.

  • Chemokines also target tumour cells and stromal cells, and they regulate tumour angiogenesis, stemness, proliferation and survival.

  • Chemokine expression is regulated intrinsically by epigenetic and genetic pathways, and also extrinsically by hypoxia, metabolic cues and the microbiota.

  • Targeting chemokine networks may alter tumour biological and immunological phenotypes, and increase antitumour immune responses.

  • Therapies that target chemokines could synergize with existing cancer therapies, including current immunotherapies.

Abstract

The tumour microenvironment is the primary location in which tumour cells and the host immune system interact. Different immune cell subsets are recruited into the tumour microenvironment via interactions between chemokines and chemokine receptors, and these populations have distinct effects on tumour progression and therapeutic outcomes. In this Review, we focus on the main chemokines that are found in the human tumour microenvironment; we elaborate on their patterns of expression, their regulation and their roles in immune cell recruitment and in cancer and stromal cell biology, and we consider how they affect cancer immunity and tumorigenesis. We also discuss the potential of targeting chemokine networks, in combination with other immunotherapies, for the treatment of cancer.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Chemokine receptor and ligand pairings.
Figure 2: The promotion of tumour immunity by chemokines.
Figure 3: Pro-tumour effects of chemokines.
Figure 4: The relationship between, and mechanisms that underlie, tumour immune phenotype and biological phenotype.

References

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  3. Balkwill, F. Cancer and the chemokine network. Nat. Rev. Cancer 4, 540–550 (2004). This is a comprehensive review of chemokines and chemokine receptors and their roles in tumour development.

    CAS  PubMed  Google Scholar 

  4. Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat. Rev. Cancer 5, 263–274 (2005). This thorough review highlights tumour and immune interactions that create an immunosuppressive and tolerizing microenvironment, and describes how their manipulation can influence therapeutic outcomes.

    CAS  PubMed  Google Scholar 

  5. Zou, W. Regulatory T cells, tumour immunity and immunotherapy. Nat. Rev. Immunol. 6, 295–307 (2006).

    CAS  PubMed  Google Scholar 

  6. Wei, S., Kryczek, I. & Zou, W. Regulatory T-cell compartmentalization and trafficking. Blood 108, 426–431 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Zou, W. & Chen, L. Inhibitory B7-family molecules in the tumour microenvironment. Nat. Rev. Immunol. 8, 467–477 (2008).

    CAS  PubMed  Google Scholar 

  8. Zou, W. & Restifo, N. P. TH17 cells in tumour immunity and immunotherapy. Nat. Rev. Immunol. 10, 248–256 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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). This is a recent review on PD1 and PDL1 that describes checkpoint blockade mechanisms, manipulation of PD1–PDL1 signalling and the influence of checkpoint blockade on therapeutic outcomes.

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Homey, B., Muller, A. & Zlotnik, A. Chemokines: agents for the immunotherapy of cancer? Nat. Rev. Immunol. 2, 175–184 (2002).

    CAS  PubMed  Google Scholar 

  13. Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003). This key paper shows that the infiltration of CD3+ T cells in ovarian cancer improves clinical outcome and positively associates with the intratumoural expression of IFNγ, IL-2 and chemokines.

    CAS  PubMed  Google Scholar 

  14. Pages, F. et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N. Engl. J. Med. 353, 2654–2666 (2005). Reference 14 demonstrates that the infiltration of effector memory T cells in colon cancer correlates with a lack of metastasis and prolonged survival. References 13 and 14 highlight the importance of T cell infiltration in improving clinical outcome.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  19. Wang, W. et al. Effector T cells abrogate stroma-mediated chemoresistance in ovarian cancer. Cell 165, 1092–1105 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  21. Kryczek, I. et al. Induction of IL-17+ T cell trafficking and development by IFN-γ: mechanism and pathological relevance in psoriasis. J. Immunol. 181, 4733–4741 (2008). This study shows how T H 1 cell-derived IFNγ can induce human IL-17+ T cells to migrate into an inflammatory microenvironment.

    CAS  PubMed  Google Scholar 

  22. Kryczek, I. et al. Human TH17 cells are long-lived effector memory cells. Sci. Transl Med. 3, 104ra100 (2011).

    PubMed  PubMed Central  Google Scholar 

  23. Muranski, P. et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood 112, 362–373 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Martin-Orozco, N. et al. T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity 31, 787–798 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  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). Using an ovarian cancer model, the authors of this paper show that cancer-derived CXCL12 directly recruits plasmacytoid DC precursor cells and that tumour-associated plasmacytoid DCs weaken immunity by inducing the development of IL-10+ T cells.

    CAS  PubMed  Google Scholar 

  26. Kryczek, I. et al. CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. Cancer Res. 65, 465–472 (2005). This paper describes a novel angiogenesis strategy in which hypoxia-induced VEGF and CXCL12 production in ovarian cancer cells synergistically induces angiogenesis and vascular endothelial cell survival.

    CAS  PubMed  Google Scholar 

  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). This study demonstrates that the intratumoural and peritumoural localization of immature myeloid DCs is mediated by the CCL20–CCR6 chemokine axis in breast cancer tissue.

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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). This study reveals the pro-tumour roles of T H 22 cells in the tumour microenvironment. These cells traffic into the colon tumour microenvironment via CCR6–CCL20 signalling, and directly increase cancer stemness via IL-22 secretion and DOT1L-mediated epigenetic mechanisms.

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Sun, D. et al. Th22 cells control colon tumorigenesis through STAT3 and Polycomb repression complex 2 signaling. Oncoimmunology 5, e1082704 (2016).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Huber, S. et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491, 259–263 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  39. Facciabene, A. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475, 226–230 (2011).

    CAS  PubMed  Google Scholar 

  40. Zhao, E. et al. Bone marrow and the control of immunity. Cell. Mol. Immunol. 9, 11–19 (2012).

    CAS  PubMed  Google Scholar 

  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). This study helps to explain why cancers metastasize to the bone marrow. It shows that T reg cells traffic into the bone marrow via CXCR4-mediated signalling and create an immunosuppressive microenvironment that supports tumour metastasis.

    CAS  PubMed  Google Scholar 

  42. Zhao, E. et al. Regulatory T cells in the bone marrow microenvironment in patients with prostate cancer. Oncoimmunology 1, 152–161 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kryczek, I. et al. Inflammatory regulatory T cells in the microenvironments of ulcerative colitis and colon carcinoma. Oncoimmunology 5, e1105430 (2016).

    PubMed  PubMed Central  Google Scholar 

  44. Kryczek, I. et al. IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer. J. Immunol. 186, 4388–4395 (2011).

    CAS  PubMed  Google Scholar 

  45. Berzofsky, J. A. & Terabe, M. NKT cells in tumor immunity: opposing subsets define a new immunoregulatory axis. J. Immunol. 180, 3627–3635 (2008).

    CAS  PubMed  Google Scholar 

  46. Kim, C. H., Johnston, B. & Butcher, E. C. Trafficking machinery of NKT cells: shared and differential chemokine receptor expression among Vα24+Vβ11+ NKT cell subsets with distinct cytokine-producing capacity. Blood 100, 11–16 (2002). This paper defines the differential chemokine receptor expression of different NKT cell subsets that facilitates their migration into inflammatory tissues.

    CAS  PubMed  Google Scholar 

  47. Metelitsa, L. S. et al. Natural killer T cells infiltrate neuroblastomas expressing the chemokine CCL2. J. Exp. Med. 199, 1213–1221 (2004). This is one of the few papers showing how NKT cells can migrate into tumours in response to CCL2.

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Nelson, B. H. CD20+ B cells: the other tumor-infiltrating lymphocytes. J. Immunol. 185, 4977–4982 (2010).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  54. Andreu, P. et al. FcRγ activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17, 121–134 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Yang, C. et al. B cells promote tumor progression via STAT3 regulated-angiogenesis. PLoS ONE 8, e64159 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Affara, N. I. et al. B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas. Cancer Cell 25, 809–821 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Mizoguchi, A. & Bhan, A. K. A case for regulatory B cells. J. Immunol. 176, 705–710 (2006).

    CAS  PubMed  Google Scholar 

  58. Banchereau, J. & Palucka, A. K. Dendritic cells as therapeutic vaccines against cancer. Nat. Rev. Immunol. 5, 296–306 (2005).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Fushimi, T., Kojima, A., Moore, M. A. & Crystal, R. G. Macrophage inflammatory protein 3α transgene attracts dendritic cells to established murine tumors and suppresses tumor growth. J. Clin. Invest. 105, 1383–1393 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  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). References 61 and 62 highlight the importance of CXCL14 and CCL20 in myeloid DC migration into and activation within tumours.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  64. Wei, S. et al. Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Res. 65, 5020–5026 (2005).

    CAS  PubMed  Google Scholar 

  65. Curiel, T. J. et al. Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer. Cancer Res. 64, 5535–5538 (2004).

    CAS  PubMed  Google Scholar 

  66. Qian, B. Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011). This paper shows that inhibition of the CCL2–CCR2 axis reduces macrophage recruitment and tumour metastasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer 4, 71–78 (2004).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Denardo, D. G. et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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). This study demonstrates the importance of CCL2 signalling in macrophage tumour biology.

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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). This paper reveals that CD68+ macrophage infiltration is positively associated with a better clinical outcome, and that the pro-tumorigenic and antitumorigenic roles of macrophages may depend on cancer cell–macrophage subset contact.

    CAS  PubMed  Google Scholar 

  80. Asano, K. et al. CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens. Immunity 34, 85–95 (2011).

    CAS  PubMed  Google Scholar 

  81. De Palma, M. & Lewis, C. E. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23, 277–286 (2013).

    CAS  PubMed  Google Scholar 

  82. Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  85. Marigo, I. et al. Tumor-induced tolerance and immune suppression depend on the C/EBPβ transcription factor. Immunity 32, 790–802 (2010).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Pollard, J. W. Trophic macrophages in development and disease. Nat. Rev. Immunol. 9, 259–270 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Waugh, D. J. J. & Wilson, C. The interleukin-8 pathway in cancer. Clin. Cancer Res. 14, 6735–6741 (2008).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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). This study demonstrates the pro-tumour role of tumour-derived CCL2 on endothelial cell permeability and thus metastasis.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  96. Bonapace, L. et al. Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature 515, 130–133 (2014). This thought-provoking study emphasizes the detrimental effects of therapy targeting a single chemokine. Even though CCL2 neutralization reduces metastasis by reducing macrophage infiltration, the cessation of this blockade leads to rapid metastasis and increased monocyte infiltration into the metastatic tumour.

    CAS  PubMed  Google Scholar 

  97. Robinson, S. C., Scott, K. A. & Balkwill, F. R. Chemokine stimulation of monocyte matrix metalloproteinase-9 requires endogenous TNF-α. Eur. J. Immunol. 32, 404–412 (2002).

    CAS  PubMed  Google Scholar 

  98. Stamenkovic, I. Matrix metalloproteinases in tumor invasion and metastasis. Semin. Cancer Biol. 10, 415–433 (2000).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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). This paper highlights the importance of CCL5 in increasing the invasiveness and migration of ovarian cancer stem-like cells.

    CAS  PubMed  Google Scholar 

  102. Zou, W. & Wicha, M. S. Chemokines and cellular plasticity of ovarian cancer stem cells. Oncoscience 2, 615–616 (2015).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Chen, J. et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell 19, 541–555 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Wang, Q. et al. CCL18 from tumor-cells promotes epithelial ovarian cancer metastasis via mTOR signaling pathway. Mol. Carcinog. 55, 1688–1699 (2016).

    CAS  PubMed  Google Scholar 

  107. Lin, L. et al. CCL18 from tumor-associated macrophages promotes angiogenesis in breast cancer. Oncotarget 6, 34758–34773 (2015).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  109. Chen, G. et al. CC chemokine ligand 18 correlates with malignant progression of prostate cancer. Biomed Res. Int. 2014, 230183 (2014).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  112. Vulcano, M. et al. Unique regulation of CCL18 production by maturing dendritic cells. J. Immunol. 170, 3843–3849 (2003).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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). This study is one of the first to define a non-chemotactic effect of CCL18 on DCs; CCL18 promotes the differentiation of tolerogenic DCs, and this immunosuppressive effect may occur within tumours.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  121. Tu, Z. et al. CCR9 in cancer: oncogenic role and therapeutic targeting. J. Hematol. Oncol. 9, 10 (2016).

    PubMed  PubMed Central  Google Scholar 

  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). This study demonstrates that CCL25 has a direct, CCR9-dependent role in breast cancer tumorigenesis.

    PubMed  Google Scholar 

  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). This study shows that in cutaneous melanoma cells, active CCR9 signalling may help to promote metastasis to the small intestine.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Letsch, A. et al. Functional CCR9 expression is associated with small intestinal metastasis. J. Invest. Dermatol. 122, 685–690 (2004).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  128. Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008).

    CAS  PubMed  Google Scholar 

  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). This study shows that CXCL8-mediated signalling is important for cancer cell biology. It explains how CXCL8-mediated signalling can promote prostate cancer cell survival in hypoxic environments.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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). Using CXCR1 blockade, the authors of this paper demonstrate the selective targeting and elimination of breast cancer stem cells by a CXCR1-blocking antibody and a CXCR1 inhibitor.

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  138. Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001). This review summarizes the chemokine–chemokine receptor networks in breast cancer cells and how this signalling determines metastasis localization.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  143. Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  145. Cioffi, M. et al. Identification of a distinct population of CD133+CXCR4+ cancer stem cells in ovarian cancer. Sci. Rep. 5, 10357 (2015).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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). This is one of the first papers to demonstrate that the orphan chemokine receptor CXCR7 mediates signalling in response to the binding of CXCL12 in T cells and thereby induces chemotaxis.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Sun, X. et al. CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev. 29, 709–722 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Wente, M. N. et al. CXCL14 expression and potential function in pancreatic cancer. Cancer Lett. 259, 209–217 (2008).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  158. Gu, X. L. et al. Expression of CXCL14 and its anticancer role in breast cancer. Breast Cancer Res. Treat. 135, 725–735 (2012).

    CAS  PubMed  Google Scholar 

  159. Sleeman, M. A. et al. B cell- and monocyte-activating chemokine (BMAC), a novel non-ELR α-chemokine. Int. Immunol. 12, 677–689 (2000).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Allinen, M. et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6, 17–32 (2004).

    CAS  PubMed  Google Scholar 

  162. Weinstein, E. J. et al. VCC-1, a novel chemokine, promotes tumor growth. Biochem. Biophys. Res. Commun. 350, 74–81 (2006).

    CAS  PubMed  Google Scholar 

  163. Matsui, A. et al. CXCL17 expression by tumor cells recruits CD11b+Gr1highF4/80 cells and promotes tumor progression. PLoS ONE 7, e44080 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  167. Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2007).

    CAS  PubMed  Google Scholar 

  168. Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Strieter, R. M., Kunkel, S. L., Arenberg, D. A., Burdick, M. D. & Polverini, P. J. Interferon-γ-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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  172. Peng, D. et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249–253 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  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). References 172 and 173 highlight a novel tumour-intrinsic mechanism in which epigenetic repression of chemokine production is mediated by PRC2, which regulates antitumour T cell infiltration, and thus tumour immunity and immunotherapy.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015). This is an important paper that reveals how tumour-intrinsic β-catenin signalling controls and inhibits T cell infiltration by suppressing DC recruitment.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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). This is the first report of a CXCR4 mutation in cancer cells that leads to functionally active CXCR4 signalling in response to CXCL12; this mutation actually slows tumour growth.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Semenza, G. L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3, 721–732 (2003).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  184. Schioppa, T. et al. Regulation of the chemokine receptor CXCR4 by hypoxia. J. Exp. Med. 198, 1391–1402 (2003). This paper details how CXCR4 is regulated by hypoxia.

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Staller, P. et al. Chemokine receptor CXCR4 downregulated by von Hippel–Lindau tumour suppressor pVHL. Nature 425, 307–311 (2003).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Vetizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Kostic, A. D. et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 14, 207–215 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Maslowski, K. M. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Sommer, F. & Backhed, F. The gut microbiota — masters of host development and physiology. Nat. Rev. Microbiol. 11, 227–238 (2013).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. McCabe, M. T. et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492, 108–112 (2012).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  202. Wrangle, J. et al. Alterations of immune response of non-small cell lung cancer with azacytidine. Oncotarget 4, 2067–2079 (2013).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  205. Bertolini, F. et al. CXCR4 neutralization, a novel therapeutic approach for non-Hodgkin's lymphoma. Cancer Res. 62, 3106–3112 (2002).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Liang, Z. et al. Silencing of CXCR4 blocks breast cancer metastasis. Cancer Res. 65, 967–971 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  212. Fridlender, Z. G. et al. CCL2 blockade augments cancer immunotherapy. Cancer Res. 70, 109–118 (2010).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Google Scholar 

Download references

Acknowledgements

The authors thank their former and current collaborators and trainees for their intellectual input and hard work. The work described in this Review was supported by grants from the US National Institutes of Health (NIH; F31CA189440) and the Herman and Dorothy Miller Award for Innovative Immunology Research to N.N.; NIH grants CA193136, CA190176, CA171306, CA152470, CA099985, CA156685, CA123088, CA133620, CA092562, CA100227 and CA211016 to W.Z.; and NIH grant R35 CA129765 to M.S.W. The Review focuses mainly on the human cancer immune microenvironment and cancer patient-oriented studies. Owing to the plethora of literature related to the topic described in this Review, the writing of a complete and extensive article is extremely challenging. The authors apologize in advance for any inadvertent omissions.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Max S. Wicha or Weiping Zou.

Ethics declarations

Competing interests

W.Z. is a consultant to NGM Bio and Lycera, and has received research grants from Medimmune, NGM Bio and Lycera. M.S.W. is a co-founder of, and holds equity in, Oncomed Pharmaceuticals, and serves as a consultant for MedImmune and Verastem. N.N. declares no competing interests.

PowerPoint slides

Glossary

Cancer stem-like cell

A cell that can self-propagate, is less-differentiated and can give rise to other tumour cells. These properties enable these cells to be potentially key players in tumour initiation, metastasis, and treatment resistance and/or cancer relapse.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nagarsheth, N., Wicha, M. & Zou, W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 17, 559–572 (2017). https://doi.org/10.1038/nri.2017.49

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri.2017.49

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer