期刊
CANCER RESEARCH
卷 82, 期 20, 页码 3774-3784出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-22-0970
关键词
-
类别
资金
- Merck -Melanoma Research Alliance Young Investigator Award
- V Foundation for Cancer Research Scholar Grant
- Sun Melanoma Research Scholar Award
- Brigham Research Institute
- Harvard Stem Cell Institute
- Brigham and Women's Hospital
- NIH/NCI grants [R01CA247957, R01CA258637, R01CA190838]
- Mizutani Foundation for Glycoscience Research Grant, NIH/NCI grant [U01CA225644]
- NIH/NIAID grant [R21AI146368]
- Walter Benjamin Fellowship from the German Research Foundation (DFG)
- Martin Mihm Fellowship from the German Society of Dermatopathology
- DFG [EXC 2151]
Tim-3 is an intrinsic growth-suppressive receptor in melanoma cells, and blocking it may promote MAPK-dependent tumorigenesis, counteracting the antitumor activity of T-cell-directed Tim-3 inhibition.
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. Inhi-bition of melanoma cell-Tim-3 promoted tumor growth in both immunocompetent and immunocompromised mice, while mel-anoma-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 mel-anomas in T-cell-deficient mice, confirming growth-promoting effects of melanoma-Tim-3 antagonism. Melanoma-Tim-3 acti-vation 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.Significance: 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据