Top

Published in:

01-12-2018 | Focussed Research Review

The role of CCR5 in directing the mobilization and biological function of CD11b⁺Gr1⁺Ly6C^low polymorphonuclear myeloid cells in cancer

Authors: Nathan Karin, Hila Razon

Published in: Cancer Immunology, Immunotherapy | Issue 12/2018

Abstract

Bone marrow (BM) cells of the hematopoietic system, also known as BM-derived leukocytes (BMD), are mobilized from the BM to the blood and then colonize tumor sites. These cells then become key players in either promoting or regulating the development and progression of tumors. Among the cells that suppress anti-tumor immunity are regulatory T cells (T_regs), tumor-associated macrophages (TAMS) and myeloid-derived suppressor cells (MDSC). MDSC comprise CD11b⁺Gr1⁺Ly6C^low polymorphonuclear myeloid cells (PMN-MDSC), and CD11b⁺Gr1⁺Ly6C^high monocytic myeloid cells (Mo-MDSC). Several studies including ours have identified the CCR2–CCL2 axis as the key driver of the mobilization of monocytic cells from the BM to the blood and later their colonization at the tumor site. The current review focuses on the mechanisms by which PMN-MDSC are mobilized from the BM to the blood and later to the tumor site, and their clinical implications.

Klein-Goldberg A, Maman S, Witz IP (2014) The role played by the microenvironment in site-specific metastasis. Cancer Lett 352(1):54–58CrossRef

Witz IP (2009) The tumor microenvironment: the making of a paradigm. Cancer Microenviron 2(Suppl 1):9–17CrossRef

Alderton GK, Bordon Y (2012) Tumour immunotherapy–leukocytes take up the fight. Nat Rev Immunol 12(4):237CrossRef

Bordon Y (2014) Tumour immunology: Anticancer drugs need bugs. Nat Rev Immunol 14(1):1CrossRef

Danovi S (2016) Tumour microenvironment: As time goes by. Nat Rev Cancer 16(6):342–343CrossRef

Dart A (2018) Tumour microenvironment: Radical changes. Nat Rev Cancer 18(2):65CrossRef

Engblom C, Pfirschke C, Pittet MJ (2016) The role of myeloid cells in cancer therapies. Nat Rev Cancer 16(7):447–462CrossRef

Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12(4):253–268CrossRef

Kitamura T, Qian BZ, Pollard JW (2015) Immune cell promotion of metastasis. Nat Rev Immunol 15(2):73–86CrossRef

10.

Nagarsheth N, Wicha MS, Zou W (2017) Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 17(9):559–572CrossRef

11.

Speiser DE, Ho PC, Verdeil G (2016) Regulatory circuits of T cell function in cancer. Nat Rev Immunol 16(10):599–611CrossRef

12.

Turley SJ, Cremasco V, Astarita JL (2015) Immunological hallmarks of stromal cells in the tumour microenvironment. Nat Rev Immunol 15(11):669–682CrossRef

13.

Yu H, Kortylewski M, Pardoll D (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7(1):41–51CrossRef

14.

Zou W (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6(4):295–307CrossRef

15.

Serbina NV, Pamer EG (2006) Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol 7(3):311–317CrossRef

16.

Umansky V, Sevko A (2012) Overcoming immunosuppression in the melanoma microenvironment induced by chronic inflammation. Cancer Immunol Immunother 61(2):275–282CrossRef

17.

Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3):162–174CrossRef

18.

Kumar V, Patel S, Tcyganov E, Gabrilovich DI (2016) The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol 37(3):208–220CrossRef

19.

Pattabiraman DR, Weinberg RA (2014) Tackling the cancer stem cells—what challenges do they pose? Nat Rev Drug Discov 13(7):497–512CrossRef

20.

Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, Mandruzzato S, Murray PJ, Ochoa A, Ostrand-Rosenberg S, Rodriguez PC, Sica A, Umansky V, Vonderheide RH, Gabrilovich DI (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7:12150CrossRef

21.

Sharma P, Allison JP (2015) Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161(2):205–214CrossRef

22.

Tanaka A, Sakaguchi S (2017) Regulatory T cells in cancer immunotherapy. Cell Res 27(1):109–118CrossRef

23.

Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, Guo B, Herbert DR, Bulfone A, Trentini F, Di Serio C, Bacchetta R, Andreani M, Brockmann L, Gregori S, Flavell RA, Roncarolo MG (2013) Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med 19(6):739–746CrossRef

24.

Biswas SK, Mantovani A (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11(10):889–896CrossRef

25.

Butler JM, Kobayashi H, Rafii S (2010) Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat Rev Cancer 10(2):138–146CrossRef

26.

Gabrilovich D (2004) Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol 4(12):941–952CrossRef

27.

Hawila E, Razon H, Wildbaum G, Blattner C, Sapir Y, Shaked Y, Umansky V, Karin N (2017) CCR5 directs the mobilization of CD11b(+)Gr1(+)Ly6C(low) polymorphonuclear myeloid cells from the bone marrow to the blood to support tumor development. Cell Rep 21(8):2212–2222CrossRef

28.

Blattner C, Fleming V, Weber R, Himmelhan B, Altevogt P, Gebhardt C, Schulze TJ, Razon H, Hawila E, Wildbaum G, Utikal J, Karin N, Umansky V (2018) CCR5(+) myeloid-derived suppressor cells are enriched and activated in melanoma lesions. Cancer Res 78(1):157–167CrossRef

29.

Bonavita O, Massara M, Bonecchi R (2016) Chemokine regulation of neutrophil function in tumors. Cytokine Growth Factor Rev 30:81–86CrossRef

30.

Sokol CL, Luster AD (2015) The chemokine system in innate immunity. Cold Spring Harb Perspect Biol 7(5):a016303. https://doi.org/10.1101/cshperspect.a016303 CrossRefPubMedPubMedCentral

31.

Zlotnik A (2006) Involvement of chemokine receptors in organ-specific metastasis. Contrib Microbiol 13:191–199CrossRef

32.

Zlotnik A, Burkhardt AM, Homey B (2011) Homeostatic chemokine receptors and organ-specific metastasis. Nat Rev Immunol 11(9):597–606CrossRef

33.

Sallusto F, Baggiolini M (2008) Chemokines and leukocyte traffic. Nat Immunol 9(9):949–952CrossRef

34.

Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19(1):71–82CrossRef

35.

Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, Kaiser EA, Snyder LA, Pollard JW (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475(7355):222–225CrossRef

36.

Izhak L, Wildbaum G, Zohar Y, Anunu R, Klapper L, Elkeles A, Seagal J, Yefenof E, Ayalon-Soffer M, Karin N (2009) A novel recombinant fusion protein encoding a 20-amino acid residue of the third extracellular (E3) domain of CCR2 neutralizes the biological activity of CCL2. J Immunol 183(1):732–739CrossRef

37.

Shojaei F, Wu X, Zhong C, Yu L, Liang XH, Yao J, Blanchard D, Bais C, Peale FV, van Bruggen N, Ho C, Ross J, Tan M, Carano RA, Meng YG, Ferrara N (2007) Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450(7171):825–831CrossRef

38.

Zhao W, Xu Y, Xu J, Wu D, Zhao B, Yin Z, Wang X (2015) Subsets of myeloid-derived suppressor cells in hepatocellular carcinoma express chemokines and chemokine receptors differentially. Int Immunopharmacol 26(2):314–321CrossRef

39.

Chang AL, Miska J, Wainwright DA, Dey M, Rivetta CV, Yu D, Kanojia D, Pituch KC, Qiao J, Pytel P, Han Y, Wu M, Zhang L, Horbinski CM, Ahmed AU, Lesniak MS (2016) CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells. Cancer Res 76(19):5671–5682CrossRef

40.

Chun E, Lavoie S, Michaud M, Gallini CA, Kim J, Soucy G, Odze R, Glickman JN, Garrett WS (2015) CCL2 promotes colorectal carcinogenesis by enhancing polymorphonuclear myeloid-derived suppressor cell population and function. Cell Rep 12(2):244–257CrossRef

41.

Ding Y, Shen J, Zhang G, Chen X, Wu J, Chen W (2015) CD40 controls CXCR5-induced recruitment of myeloid-derived suppressor cells to gastric cancer. Oncotarget 6(36):38901–38911CrossRef

42.

Highfill SL, Cui Y, Giles AJ, Smith JP, Zhang H, Morse E, Kaplan RN, Mackall CL (2014) Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med 6(237):237ra267CrossRef

43.

Katoh H, Wang D, Daikoku T, Sun H, Dey SK, Dubois RN (2013) CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis. Cancer Cell 24(5):631–644CrossRef

44.

Lesokhin AM, Hohl TM, Kitano S, Cortez C, Hirschhorn-Cymerman D, Avogadri F, Rizzuto GA, Lazarus JJ, Pamer EG, Houghton AN, Merghoub T, Wolchok JD (2012) Monocytic CCR2(+) myeloid-derived suppressor cells promote immune escape by limiting activated CD8 T-cell infiltration into the tumor microenvironment. Cancer Res 72(4):876–886CrossRef

45.

Ortiz ML, Lu L, Ramachandran I, Gabrilovich DI (2014) Myeloid-derived suppressor cells in the development of lung cancer. Cancer Immunol Res 2(1):50–58CrossRef

46.

Saiwai H, Kumamaru H, Ohkawa Y, Kubota K, Kobayakawa K, Yamada H, Yokomizo T, Iwamoto Y, Okada S (2013) Ly6C+Ly6G-myeloid-derived suppressor cells play a critical role in the resolution of acute inflammation and the subsequent tissue repair process after spinal cord injury. J Neurochem 125(1):74–88CrossRef

47.

Wang D, Sun H, Wei J, Cen B, DuBois RN (2017) CXCL1 is critical for premetastatic niche formation and metastasis in colorectal cancer. Cancer Res 77(13):3655–3665CrossRef

48.

Zhang H, Ye YL, Li MX, Ye SB, Huang WR, Cai TT, He J, Peng JY, Duan TH, Cui J, Zhang XS, Zhou FJ, Wang RF, Li J (2017) CXCL2/MIF-CXCR2 signaling promotes the recruitment of myeloid-derived suppressor cells and is correlated with prognosis in bladder cancer. Oncogene 36(15):2095–2104CrossRef

Title: The role of CCR5 in directing the mobilization and biological function of CD11b+Gr1+Ly6Clow polymorphonuclear myeloid cells in cancer
Authors: Nathan Karin
Hila Razon
Publication date: 01-12-2018
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 12/2018
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-018-2245-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 12/2018

Cystatin F as a regulator of immune cell cytotoxicity

Anergic natural killer cells educated by tumor cells are associated with a poor prognosis in patients with advanced pancreatic ductal adenocarcinoma

Myeloid-derived suppressor cells (MDSCs) in patients with solid tumors: considerations for granulocyte colony-stimulating factor treatment

A phase I/randomized phase II study of GM.CD40L vaccine in combination with CCL21 in patients with advanced lung adenocarcinoma

Tumor lysate-based vaccines: on the road to immunotherapy for gallbladder cancer

Splice variants of human natural cytotoxicity receptors: novel innate immune checkpoints

Keynote webinar | Spotlight on antibody–drug conjugates in cancer