PMID:23867499

Citation	Cook, RS, Jacobsen, KM, Wofford, AM, DeRyckere, D, Stanford, J, Prieto, AL, Redente, E, Sandahl, M, Hunter, DM, Strunk, KE, Graham, DK and Earp, HS 3rd (2013) MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis. J. Clin. Invest. 123:3231-42
Abstract	MerTK, a receptor tyrosine kinase (RTK) of the TYRO3/AXL/MerTK family, is expressed in myeloid lineage cells in which it acts to suppress proinflammatory cytokines following ingestion of apoptotic material. Using syngeneic mouse models of breast cancer, melanoma, and colon cancer, we found that tumors grew slowly and were poorly metastatic in MerTK-/- mice. Transplantation of MerTK-/- bone marrow, but not wild-type bone marrow, into lethally irradiated MMTV-PyVmT mice (a model of metastatic breast cancer) decreased tumor growth and altered cytokine production by tumor CD11b+ cells. Although MerTK expression was not required for tumor infiltration by leukocytes, MerTK-/- leukocytes exhibited lower tumor cell-induced expression of wound healing cytokines, e.g., IL-10 and growth arrest-specific 6 (GAS6), and enhanced expression of acute inflammatory cytokines, e.g., IL-12 and IL-6. Intratumoral CD8+ T lymphocyte numbers were higher and lymphocyte proliferation was increased in tumor-bearing MerTK-/- mice compared with tumor-bearing wild-type mice. Antibody-mediated CD8+ T lymphocyte depletion restored tumor growth in MerTK-/- mice. These data demonstrate that MerTK signaling in tumor-associated CD11b+ leukocytes promotes tumor growth by dampening acute inflammatory cytokines while inducing wound healing cytokines. These results suggest that inhibition of MerTK in the tumor microenvironment may have clinical benefit, stimulating antitumor immune responses or enhancing immunotherapeutic strategies.
Links	PubMed PMC3726162 Online version:10.1172/JCI67655
Keywords	Animals; CD8-Positive T-Lymphocytes/enzymology; Colonic Neoplasms/enzymology; Colonic Neoplasms/immunology; Colonic Neoplasms/pathology; Cytokines/genetics; Cytokines/metabolism; Disease Resistance/immunology; Female; Gene Expression Regulation, Neoplastic; Leukocytes/enzymology; Male; Mammary Neoplasms, Experimental/enzymology; Mammary Neoplasms, Experimental/immunology; Mammary Neoplasms, Experimental/pathology; Melanoma, Experimental/enzymology; Melanoma, Experimental/immunology; Melanoma, Experimental/pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasm Transplantation; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Transcriptome; Tumor Burden; Tumor Microenvironment
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:MERTK	Contributes to	GO:0002834: regulation of response to tumor cell	ECO:0000316:		P		Figure 1 Mice with MerTK–/– microenvironment experienced decreased tumor malignancy.	Missing: with/from CACAO 9372

References

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