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

ESDR467 - Tim-3 is a growth-suppressive immune checkpoint receptor intrinsic to melanoma cells

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.