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.

Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution

“…These findings are consistent with previous reports indicating that loss of MerTK or its ligand Gas6 decreases tumor malignancy in transplantable tumor models in virgin mice, without affecting macrophage recruitment to tumors (31,63). The previous studies reported that adoptive transfer of MerTK-deficient bone marrow reduced tumor growth over the course of 20 weeks and altered tumor cytokine levels, although lung metastasis and efferocytosis were not reported in this model (31). Together, the current and previous studies suggest that MerTK inhibition reduces tumor malignancy through impaired efferocytosisinduced cytokine modulation.…”

“…Thus, our studies provide the first illustration to our knowledge of how efferocytosis promotes malignant cancer progression in the endogenous TME. These findings are consistent with previous reports indicating that loss of MerTK or its ligand Gas6 decreases tumor malignancy in transplantable tumor models in virgin mice, without affecting macrophage recruitment to tumors (31,63). The previous studies reported that adoptive transfer of MerTK-deficient bone marrow reduced tumor growth over the course of 20 weeks and altered tumor cytokine levels, although lung metastasis and efferocytosis were not reported in this model (31).…”

“…Dead cell bodies in MerTK -/-tumors remained prominent throughout postpartum Inv d40 ( Figure 2J). Because we did not observe increased TUNEL staining in mammary tumors from virgin MerTK -/-mice (Supplemental Figure 5E) and because previous studies demonstrate that MerTK is poorly expressed in MMTV PyVmT tumor cells (31), these data suggest that MerTK loss did not increase tumor cell death per se, but caused an accumulation of dead cell bodies throughout postpartum involution due to a failure in efferocytosis. This is supported by annexin V staining of purified, cultured MerTK +/+ PyVmT and MerTK -/-PyVmT primary tumor cells, which revealed similar levels of cell death in both groups (Supplemental Figure 5G).…”

“…Macrophages require the RTK MerTK to engulf dying cells, particularly during postpartum involution, when dying cells are previous work shows that MerTK, an RTK required for efficient efferocytosis by macrophages and epithelial cells, is elevated during postpartum involution (30) and is involved in the accumulation of Th2-like tumor-associated leukocytes in preclinical mammary tumor models (31).…”

The TAM family as a therapeutic target in combination with radiation therapy

“…However, non-cancer cell expression of Mertk can influence tumor growth. In Mertk −/− hosts, MMTV-PyMT orthotopic grafts show delayed tumor growth, decreased pulmonary metastases, increased expression of proinflammatory cytokines IL-6 and IL-12 and increased infiltration of CD8 + T cells, suggesting a role for Mertk in early tumor development [54]. This is not true in all models, as CT26 colorectal carcinoma and 4T1 mammary carcinoma in BALB/c mice, and Panc02 pancreatic adenocarcinoma, 3LL lung adenocarcinoma and B16 melanoma in C57BL/6 mice backgrounds were not different between wild-type and Mertk −/− hosts [42].…”