Inhibition of melanoma cell-intrinsic Tim-3 stimulates MAPK-dependent tumorigenesis.

Schatton, Tobias; Itoh, Yuta; Martins, Christina; Rasbach, Erik; Singh, Praveen; Silva, Mariana; Mucciarone, Kyla N; Heppt, Markus V; Geddes-Sweeney, Jenna; Stewart, Kate; Brandenburg, Anne; Liang, Jennifer; Dimitroff, Charles J; Mihm, Martin C; Landsberg, Jennifer; Schlapbach, Christoph; Lian, Christine G; Murphy, George F; Kupper, Thomas S; Ramsey, Matthew R; ... (2022). Inhibition of melanoma cell-intrinsic Tim-3 stimulates MAPK-dependent tumorigenesis. Cancer research, 82(20), pp. 3774-3784. American Association for Cancer Research AACR 10.1158/0008-5472.CAN-22-0970

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T-cell immunoglobulin and mucin domain 3 (Tim-3) is an immune checkpoint receptor that dampens effector functions and causes terminal exhaustion of cytotoxic T-cells. Tim-3 inhibitors are under investigation in immuno-oncology (IO) trials, because 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 cell-Tim-3 promoted tumor growth in both immunocompetent and immunocompromised mice, while melanoma-specific Tim-3 overexpression attenuated tumorigenesis. Antibody (Ab)-mediated Tim-3 blockade inhibited 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 stimulated tumorigenesis of both highly and lesser immunogenic murine and human melanomas in T-cell-deficient mice, confirming growth-promoting effects of melanoma-Tim-3 antagonism. Melanoma-Tim-3 activation suppressed, while its blockade enhanced, phosphorylation of pro-proliferative downstream mitogen-activated protein kinase (MAPK) signaling mediators. Finally, pharmacologic MAPK inhibition reversed unwanted Tim-3 Ab-mediated tumorigenesis in T-cell-deficient mice and promoted desired antitumor activity of Tim-3 interference in T-cell-competent hosts. These results identify melanoma-Tim-3 blockade as a mechanism that antagonizes T-cell-Tim-3-directed IO therapeutic efficacy. They further reveal MAPK targeting as a combination strategy for circumventing adverse consequences of unintended melanoma-Tim-3 inhibition.

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