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 2

MerTK-deficient leukocytes confer tumor resistance to MerTK+/+ mice.

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MerTK-deficient leukocytes confer tumor resistance to MerTK+/+ mice. ...
(A) Whole cell lysates harvested from MMTV-PyVmT primary mammary tumor cells were assessed by Western analysis using antibodies indicated. Whole spleen lysates harvested from MerTK+/+ and MerTK–/– mice were used as positive and negative controls, respectively, for MerTK expression. Whole spleen lysates harvested from MerTK+/+ mice were used as a positive control for AXL expression. Whole brain lysates harvested from Tyro3+/+ and Tyro3–/– mice were used as positive and negative controls from TYRO3 expression. (B–D) Bone marrow harvested from MerTK+/+ or MerTK–/– donors was delivered by tail vein injection into lethally irradiated 6-week-old female MMTV-PyVmT recipients. (B) Average tumor volume ± SEM measured in live mice by MRI at 15.8, 17.8, and 19.8 weeks of age. (C) Representative transverse MRI slices of age-matched MMTV-PyVmT recipients of MerTK+/+ or MerTK–/– bone marrow in the lower abdomen/pelvic region. The arrows indicate the location of the spine, while the tumor (T) margins are identified by the red dotted line. (D) Total tumor weight measured at 21 weeks of age (time of necropsy). Horizontal bars represent average total tumor weight ± SEM (n = 14). The P value was calculated using Student’s t test. *P < 0.05. (E) Mammary fibroblasts harvested from MerTK+/+ and MerTK–/– mice were cotransplanted with MMTV-PyVmT tumor cells into the mammary fat pads of MerTK+/+ mice, and tumor latency was measured.