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Inhibition of Melanoma Cell–Intrinsic Tim-3 Stimulates MAPK-Dependent Tumorigenesis

2022; American Association for Cancer Research; Volume: 82; Issue: 20 Linguagem: Inglês

10.1158/0008-5472.can-22-0970

1538-7445

Tobias Schatton, Yuta Itoh, Christina Martins, Erik Rasbach, Praveen Kumar Singh, Mariana Silva, Kyla Mucciarone, Markus V. Heppt, Jenna Geddes-Sweeney, Kate Stewart, Anne Brandenburg, Jennifer Liang, Charles J. Dimitroff, Martín C. Mihm, Jennifer Landsberg, Christoph Schlapbach, Christine G. Lian, Gëorge F. Murphy, Thomas S. Kupper, Matthew R. Ramsey, Steven R. Barthel,

Signaling Pathways in Disease

T-cell immunoglobulin mucin family member 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. 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 MAPK signaling mediators. Finally, pharmacologic MAPK inhibition reversed unwanted Tim-3 Ab-mediated tumorigenesis in T-cell-deficient mice and enhanced 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. Tim-3 is a growth-suppressive receptor intrinsic to melanoma cells, the blockade of which promotes MAPK-dependent tumorigenesis and thus counteracts antitumor activity of T-cell-directed Tim-3 inhibition.