The TAM family (Tyro3, Axl and MerTK) of receptor tyrosine kinases (RTKs) was one of the last families identified and one of the last to evolve. Their principal role in multicellular organisms appears to be detection of phosphatidyl serine (PtdSer) through a linking protein ligand (e.g. Gas6 or ProS) that together bind to and activate MerTK and intracellular signaling. PtdSer is exposed on the surface of aggregating platelets, exosomes and most prominently on the external surface of billions of cells that daily undergo apoptosis. The best studied homeostatic function of the family is the macrophage role of MerTK as it responds to apoptotic PtdSer by triggering ingestion (effercytosis) and signaling that this is “self-material”. This signal prevents an inflammatory macrophage response (e.g. IL-12) and polarizes the macrophage to an M2-like (e.g. IL-10, TGFb), wound healing, alternatively activated phenotype. This MerTK action is crucial for preventing autoimmunity efficiently ingesting dying cells and clearing self-antigens; this MerTK action is deleterious and immunosuppressive in tumor microenvironment (TME) and its innate immune infiltrate. TME immunosuppressive activities are stimulated by MerTK alone or in combination with Axl and Tyro 3 signaling in the innate immune cell repertoire. For example, our new data shows that all three TAM RTKs are present in Myeloid Derived Suppressor Cells and each (MerTK, Axl and Tyro 3) enhances MDSC suppressive action. MerTK activation also is key in the suppression of cross presentation by the tolerizing dendritic cell in which MerTK is substantially upregulated. In metastatic melanoma, immune checkpoint therapy has produced remarkable responses, some of which are durable. However, patients without an M1, Th1 immune infiltrate are less likely to benefit. Our overall hypothesis is that MerTK, Axl and Tyro 3 are in part responsible for the counterproductive, immunosuppressive immune infiltrate in melanoma (and other tumor types) through their innate immune cell action. This TAM RTK immunosuppressive action is probably present in most TMEs which are characterized by hypoxia, abundant apoptotic cells, and presence of secreted paracrine and autocrine TAM ligands (Gas6 and ProS). Our objective is to characterize the MerTK (and Axl, Tyro 3) signals in MDSCs, macrophages monocytes and tolerizing DCs, their downstream mechanisms and their consequences for the adaptive T reg and T eff cell responses. We will use wild type and knockout mice with preclinical syngeneic and genetically-engineered mouse melanomas as our models. We have UNC synthesized small molecule MerTK (and newer UNC TAM RTK) inhibitors as well as genetic methods to determine if inhibition of MerTK and other TAM receptors can produce an immune-modulatory tumor response. We will also test whether the combinations of immune checkpoint antibodies (anti-CTLA4 and anti-PD-1) and TAM RTK inhibitors will increase therapeutic efficacy.