467 Tim-3 is a growth-suppressive immune checkpoint receptor intrinsic to melanoma cells

T-cell immunoglobulin and mucin domain 3 (Tim-3) is an immune checkpoint target under investigation in immuno-oncology (IO) trials. Blockade of T-cell-Tim-3 enhances antitumor immunity. Here, we identify additional role for Tim-3 as a growth-suppressive receptor intrinsic to melanoma cells. Inhibition melanoma-Tim-3 by RNA interference promotes, while melanoma-specific overexpression attenuates, tumor growth both immunocompetent immunocompromised, but not ligand (Galectin-9) null mice. antibody (Ab) blockade inhibits immunogenic murine melanomas T-cell-competent hosts, consistent with established effects inhibition. In contrast, Ab administration stimulates tumorigenesis highly lesser T-cell-deficient mice, confirming growth-promoting cell-Tim-3 antagonism. Indeed, cell-intrinsic activation suppresses, enhances, phosphorylation pro-proliferative downstream signaling mediators, including mitogen-activated protein kinase (MAPK) pathway members. Finally, pharmacologic MAPK inhibition reverses the unwanted interference. Our results potential antagonist T-cell-Tim-3-directed IO therapy. We uncover targeting combination strategy that can circumvent adverse consequences unintended