Rebecca Cook
Faculty Member
Last active: 4/15/2019

MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis.

Cook RS, Jacobsen KM, Wofford AM, DeRyckere D, Stanford J, Prieto AL, Redente E, Sandahl M, Hunter DM, Strunk KE, Graham DK, Earp HS
J Clin Invest. 2013 123 (8): 3231-42

PMID: 23867499 · PMCID: PMC3726162 · DOI:10.1172/JCI67655

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.

MeSH Terms (21)

Animals c-Mer Tyrosine Kinase CD8-Positive T-Lymphocytes Colonic Neoplasms Cytokines Disease Resistance Female Gene Expression Regulation, Neoplastic Leukocytes Male Mammary Neoplasms, Experimental Melanoma, Experimental Mice Mice, Inbred C57BL Mice, Knockout Neoplasm Transplantation Proto-Oncogene Proteins Receptor Protein-Tyrosine Kinases Transcriptome Tumor Burden Tumor Microenvironment

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