title: 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.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Cook
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Jacobsen
authors.forename: Anne M
authors.initials: AM
authors.lastname: Wofford
authors.forename: Deborah
authors.initials: D
authors.lastname: DeRyckere
authors.forename: Jamie
authors.initials: J
authors.lastname: Stanford
authors.forename: Anne L
authors.initials: AL
authors.lastname: Prieto
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Redente
authors.forename: Melissa
authors.initials: M
authors.lastname: Sandahl
authors.forename: Debra M
authors.initials: DM
authors.lastname: Hunter
authors.forename: Karen E
authors.initials: KE
authors.lastname: Strunk
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Graham
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D060467:Disease Resistance / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007962:Leukocytes / Q000201:enzymology*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D008546:Melanoma, Experimental / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D059467:Transcriptome; D047368:Tumor Burden; D059016:Tumor Microenvironment; D000076202:c-Mer Tyrosine Kinase
chemical_list: D016207:Cytokines; D011518:Proto-Oncogene Proteins; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase