Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer

Proceedings of the National Academy of Sciences of the United States of America

Volumn 114, Issue 39, 2017, Pages 10455-10460

  Jung, Keehoon ^a   Heishi, Takahiro ^a   Incio, Joao ^a   Huang, Yuhui ^a   Beech, Elizabeth Y ^a   Pinter, Matthias ^a   Ho, William W ^a,b   Kawaguchi, Kosuke ^a   Rahbari, Nuh N ^a   Chung, Euiheon ^a,e   Kim, Jun Ki ^a,f   Clark, Jeffrey W ^a   Willett, Christopher G ^c   Yun, Seok Hyun ^a,d   Luster, Andrew D ^a   Padera, Timothy P ^a   Jain, Rakesh K ^a   Fukumura, Dai ^a  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b Massachusetts Institute of Technology   (United States)

^c DUKE UNIVERSITY MEDICAL CENTER   (United States)

^d MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^e Gwangju Institute of Science and Technology (GIST)   (South Korea)

^f University of Ulsan College of Medicine   (South Korea)

Author keywords

Antiangiogenic therapy; CXCR4; Ly6Clow monocyte; Tumor immunity; Tumor microenvironment

Indexed keywords

BEVACIZUMAB; CHEMOKINE RECEPTOR CXCR4; MONOCLONAL ANTIBODY DC101; PLERIXAFOR; ANGIOGENESIS INHIBITOR; CXCL12 PROTEIN, MOUSE; CXCR4 PROTEIN, MOUSE; HETEROCYCLIC COMPOUND; KDR PROTEIN, MOUSE; LY ANTIGEN; LY-6C ANTIGEN, MOUSE; LY6G ANTIGEN, MOUSE; MONOCLONAL ANTIBODY; RAMUCIRUMAB; STROMAL CELL DERIVED FACTOR 1; VASCULAR ENDOTHELIAL GROWTH FACTOR A, MOUSE; VASCULOTROPIN A; VASCULOTROPIN RECEPTOR 2;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIANGIOGENIC THERAPY; ANTINEOPLASTIC ACTIVITY; ARTICLE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL PROLIFERATION; COLORECTAL CANCER; CONTROLLED STUDY; DENDRITIC CELL; FLOW CYTOMETRY; IMMUNOPHENOTYPING; INNATE IMMUNITY; MONOCYTE; MONOTHERAPY; MOUSE; NATURAL KILLER CELL; NEUTROPHIL; NEUTROPHIL CHEMOTAXIS; NONHUMAN; PRIORITY JOURNAL; PROTEIN DEPLETION; PROTEIN TARGETING; TUMOR ASSOCIATED LEUKOCYTE; TUMOR GROWTH; TUMOR VOLUME; ANIMAL; ANTAGONISTS AND INHIBITORS; BIOSYNTHESIS; C57BL MOUSE; COLORECTAL TUMOR; IMMUNOLOGY; KNOCKOUT MOUSE; METABOLISM; TUMOR CELL CULTURE;

ANGIOGENESIS INHIBITORS; ANIMALS; ANTIBODIES, MONOCLONAL; ANTIGENS, LY; BEVACIZUMAB; CELL PROLIFERATION; CHEMOKINE CXCL12; COLORECTAL NEOPLASMS; HETEROCYCLIC COMPOUNDS; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; MONOCYTES; NEUTROPHILS; RECEPTORS, CXCR4; TUMOR CELLS, CULTURED; VASCULAR ENDOTHELIAL GROWTH FACTOR A; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2;

EID: 85029922074     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1710754114     Document Type: Article

References (55)

1. Jain RK (2014) Antiangiogenesis strategies revisited: From starving tumors to alleviating hypoxia. Cancer Cell 26:605–622.
2. Rivera LB, et al. (2015) Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy. Cell Rep 11:577–591.
3. Rahbari NN, et al. (2016) Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases. Sci Transl Med 8:360ra135.
4. Chung AS, et al. (2013) An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat Med 19:1114–1123.
5. Rivera LB, Bergers G (2015) Intertwined regulation of angiogenesis and immunity by myeloid cells. Trends Immunol 36:240–249.
6. Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8:299–309.
7. Sitohy B, Nagy JA, Dvorak HF (2012) Anti-VEGF/VEGFR therapy for cancer: Reassessing the target. Cancer Res 72:1909–1914.
8. Dvorak HF (2015) Tumor stroma, tumor blood vessels, and antiangiogenesis therapy. Cancer J 21:237–243.
9. Jung K, et al. (2017) Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy. J Clin Invest 127:3039–3051.
10. Willett CG, et al. (2009) Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: A multidisciplinary phase II study. J Clin Oncol 27:3020–3026.
11. Xu L, et al. (2009) Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer. Cancer Res 69:7905–7910.
12. Balabanian K, et al. (2012) Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice. Blood 119:5722–5730.
13. Devi S, et al. (2013) Neutrophil mobilization via plerixafor-mediated CXCR4 inhibition arises from lung demargination and blockade of neutrophil homing to the bone marrow. J Exp Med 210:2321–2336.
14. Eash KJ, Means JM, White DW, Link DC (2009) CXCR4 is a key regulator of neutrophil release from the bone marrow under basal and stress granulopoiesis conditions. Blood 113:4711–4719.
15. Liu Q, et al. (2015) CXCR4 antagonist AMD3100 redistributes leukocytes from primary immune organs to secondary immune organs, lung, and blood in mice. Eur J Immunol 45:1855–1867.
16. Martin C, et al. (2003) Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity 19:583–593.
17. Chong SZ, et al. (2016) CXCR4 identifies transitional bone marrow premonocytes that replenish the mature monocyte pool for peripheral responses. J Exp Med 213: 2293–2314.
18. Kim P, et al. (2010) In vivo wide-area cellular imaging by side-view endomicroscopy. Nat Methods 7:303–305.
19. Donzella GA, et al. (1998) AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nat Med 4:72–77.
20. Duda DG, et al. (2011) CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: An emerging sensitizer for anticancer therapies? Clin Cancer Res 17:2074–2080.
21. Yang L, et al. (2008) Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13:23–35.
22. Kumar A, et al. (2006) CXCR4 physically associates with the T cell receptor to signal in T cells. Immunity 25:213–224.
23. Thelen M (2001) Dancing to the tune of chemokines. Nat Immunol 2:129–134.
24. Hiratsuka S, et al. (2011) C-X-C receptor type 4 promotes metastasis by activating p38 mitogen-activated protein kinase in myeloid differentiation antigen (Gr-1)positive cells. Proc Natl Acad Sci USA 108:302–307.
25. Shojaei F, et al. (2007) Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol 25:911–920.
26. Nahrendorf M, et al. (2007) The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med 204: 3037–3047.
27. Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19:71–82.
28. Carlin LM, et al. (2013) Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate their disposal. Cell 153:362–375.
29. Jung S, et al. (2000) Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 20: 4106–4114.
30. Jung K, et al. (2013) Endoscopic time-lapse imaging of immune cells in infarcted mouse hearts. Circ Res 112:891–899.
31. Willett CG, et al. (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145–147.
32. Rigamonti N, et al. (2014) Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. Cell Rep 8:696–706.
33. Pardoll D (2015) Cancer and the immune system: Basic concepts and targets for intervention. Semin Oncol 42:523–538.
34. Kumar V, Patel S, Tcyganov E, Gabrilovich DI (2016) The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol 37:208–220.
35. Hanahan D, Coussens LM (2012) Accessories to the crime: Functions of cells recruited to the tumor microenvironment. Cancer Cell 21:309–322.
36. Noy R, Pollard JW (2014) Tumor-associated macrophages: From mechanisms to therapy. Immunity 41:49–61.
37. Palucka AK, Coussens LM (2016) The basis of oncoimmunology. Cell 164:1233–1247.
38. Ghosh M, et al. (2009) PPARdelta is pro-tumorigenic in a mouse model of COX-2induced mammary cancer. Prostaglandins Other Lipid Mediat 88:97–100.
39. Proia RL, Hla T (2015) Emerging biology of sphingosine-1-phosphate: Its role in pathogenesis and therapy. J Clin Invest 125:1379–1387.
40. Buchbinder EI, Hodi FS (2016) Melanoma in 2015: Immune-checkpoint blockade - durable cancer control. Nat Rev Clin Oncol 13:77–78.
41. Baumeister SH, Freeman GJ, Dranoff G, Sharpe AH (2016) Coinhibitory pathways in immunotherapy for cancer. Annu Rev Immunol 34:539–573.
42. Topalian SL, Taube JM, Anders RA, Pardoll DM (2016) Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 16:275–287.
43. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264.
44. Llosa NJ, et al. (2015) The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 5:43–51.
45. Xiao Y, Freeman GJ (2015) The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy. Cancer Discov 5:16–18.
46. Talmadge JE, Gabrilovich DI (2013) History of myeloid-derived suppressor cells. Nat Rev Cancer 13:739–752.
47. Schmid MC, Varner JA (2012) Myeloid cells in tumor inflammation. Vasc Cell 4:14.
48. Engblom C, Pfirschke C, Pittet MJ (2016) The role of myeloid cells in cancer therapies. Nat Rev Cancer 16:447–462.
49. Kaneda MM, et al. (2016) PI3Kγ is a molecular switch that controls immune suppression. Nature 539:437–442.
50. Kaneda MM, et al. (2016) Macrophage PI3Kγ drives pancreatic ductal adenocarcinoma progression. Cancer Discov 6:870–885.
51. Morimoto-Tomita M, Ohashi Y, Matsubara A, Tsuiji M, Irimura T (2005) Mouse colon carcinoma cells established for high incidence of experimental hepatic metastasis exhibit accelerated and anchorage-independent growth. Clin Exp Metastasis 22:513–521.
52. Zhang Y, Davis C, Ryan J, Janney C, Peña MM (2013) Development and characterization of a reliable mouse model of colorectal cancer metastasis to the liver. Clin Exp Metastasis 30: 903–918.
53. Chung E, et al. (2009) Secreted Gaussia luciferase as a biomarker for monitoring tumor progression and treatment response of systemic metastases. PLoS One 4:e8316.
54. Tannous BA (2009) Gaussia luciferase reporter assay for monitoring biological processes in culture and in vivo. Nat Protoc 4:582–591.
55. Huang Y, et al. (2012) Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci USA 109:17561–17566.