MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis
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
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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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 3

Altered early tumor response in MerTK-deficient mice.

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Altered early tumor response in MerTK-deficient mice. (A) Representati...
(A) Representative H&E-stained and cytokeratin-stained sections of mammary glands 4 days after injection with MMTV-PyVmT cells are shown. Boxed regions are shown at higher magnification below. Original magnification, ×100 (top row); ×600 (bottom rows). (B) Single cell mammary suspensions harvested 4 days after intramammary tumor cell injections were stained for CD11b and CD11c. Proportions of CD11b+CD11c– macrophages and CD11b+CD11c+ dendritic cells relative to total PBS-treated MerTK+/+ CD11b+CD11c+ population is shown. *P < 0.05. (C) RNA harvested 4 days after PBS, MMTV-PyVmT, or B16:F10 injection into the inguinal mammary fat pad was assessed by qPCR to detect IL-10 and IL-12p40 transcripts. (D) Serum collected 4 days after injection of PBS, MMTV-PyVmT, or B16:F10 tumor cells into the inguinal mammary fat pad was assessed by ELISA to measure IL-12p70 and IL-6. (C and D) Values shown, calculated using the (C) δδCT method or (D) serum levels, represent the average ± SD (n = 6), relative to the level detected in PBS-treated MerTK+/+ samples. *P < 0.05; **P < 0.01; ***P < 0.001. (E) Mice were inoculated with B16:F10 cells by i.p. injection. After 4 days, mice were treated with BrdU. Splenocytes harvested after 1 hour treatment with BrdU were stained with anti-BrdU and propidium iodide and assessed by flow cytometry.