MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis
Rebecca S. Cook, … , Douglas K. Graham, H. Shelton Earp III
Rebecca S. Cook, … , Douglas K. Graham, H. Shelton Earp III
Published July 8, 2013
Citation Information: J Clin Invest. 2013;123(8):3231-3242. https://doi.org/10.1172/JCI67655.
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Research Article Oncology

MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis

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.

Authors

Rebecca S. Cook, Kristen M. Jacobsen, Anne M. Wofford, Deborah DeRyckere, Jamie Stanford, Anne L. Prieto, Elizabeth Redente, Melissa Sandahl, Debra M. Hunter, Karen E. Strunk, Douglas K. Graham, H. Shelton Earp III

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Figure 1

Decreased tumor malignancy in MerTK–/– microenvironment.

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Decreased tumor malignancy in MerTK–/– microenvironment. (A) MMTV-PyVm...
(A) MMTV-PyVmT mammary tumor cells injected into the mammary fat pads and B16:F10 tumor cells injected intradermally formed tumors with a delayed latency in MerTK–/– mice as compared with that in MerTK+/+ and MerTK+/– mice. P values comparing MerTK+/+ to MerTK–/– were determined using the log-rank (Mantel-Cox) test. (B) H&E-stained sections of tumors harvested 30 days after tumor cell injection in MerTK+/+ mice and 180 days after tumor cell injection in MerTK–/– mice. Boxed regions are shown at higher magnification below and indicate the monotonous sheets of tumor cells in MerTK+/+ mice and the compartmentalized nature of the implanted tumor cells in MerTK–/– mice. Original magnification, ×100 (top row); ×600 (bottom row). (C) Lung metastases were enumerated in tumor-bearing mice at 14 days after MMTV-PyVmT tumor palpation (n = 14–16), at 7 days after B16:F10 tumor palpation (n = 5), and at 7 days after MC38 tumor palpation of subcutaneously implanted MC38 cells. Horizontal bars represent average numbers of lung metastases per mouse. P values were calculated using Student’s t test for MMTV-PyVmT tumors (comparing MerTK+/+ to MerTK–/–) and using a 1-tailed Mann-Whitney test for B16:F10 and MC38 tumors. *P < 0.05. ***P < 0.001.