MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis
| Autor: | Elizabeth F. Redente, H. Shelton Earp, Kristen M. Jacobsen, Anne M. Wofford, Karen E. Strunk, Deborah DeRyckere, Melissa Sandahl, Rebecca S. Cook, Jamie C. Stanford, Anne L. Prieto, Douglas K. Graham, Debra Hunter |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Male
Myeloid medicine.medical_treatment Melanoma Experimental Lymphocyte proliferation CD8-Positive T-Lymphocytes Biology C-Mer Tyrosine Kinase Proinflammatory cytokine Mice Proto-Oncogene Proteins Leukocytes Tumor Microenvironment medicine Animals Disease Resistance Mice Knockout Tumor microenvironment c-Mer Tyrosine Kinase GAS6 Mammary Neoplasms Experimental Receptor Protein-Tyrosine Kinases General Medicine MERTK Tumor Burden Gene Expression Regulation Neoplastic Mice Inbred C57BL Cytokine medicine.anatomical_structure Colonic Neoplasms Immunology Cancer research Cytokines Female Transcriptome Neoplasm Transplantation Research Article |
| DOI: | 10.17615/rsrx-4q11 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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