Tim-3 mediates T cell trogocytosis to limit antitumor immunity
T cell immunoglobulin mucin domain-containing protein 3 (Tim-3) negatively regulates innate and adaptive immunity in cancer. To identify the mechanisms of Tim-3 in cancer immunity, we evaluated the effects of Tim-3 blockade in human and mouse melanoma. Here, we show that human programmed cell death...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-05-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI152864 |
| _version_ | 1828807968331661312 |
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| author | Ornella Pagliano Robert M. Morrison Joe-Marc Chauvin Hridesh Banerjee Diwakar Davar Quanquan Ding Tokiyoshi Tanegashima Wentao Gao Saranya R. Chakka Richelle DeBlasio Ava Lowin Kevin Kara Mignane Ka Bochra Zidi Rada Amin Itay Raphael Shuowen Zhang Simon C. Watkins Cindy Sander John M. Kirkwood Marcus Bosenberg Ana C. Anderson Vijay K. Kuchroo Lawrence P. Kane Alan J. Korman Arvind Rajpal Sean M. West Minhua Han Christine Bee Xiaodi Deng Xiao Min Schebye Pavel Strop Hassane M. Zarour |
| author_facet | Ornella Pagliano Robert M. Morrison Joe-Marc Chauvin Hridesh Banerjee Diwakar Davar Quanquan Ding Tokiyoshi Tanegashima Wentao Gao Saranya R. Chakka Richelle DeBlasio Ava Lowin Kevin Kara Mignane Ka Bochra Zidi Rada Amin Itay Raphael Shuowen Zhang Simon C. Watkins Cindy Sander John M. Kirkwood Marcus Bosenberg Ana C. Anderson Vijay K. Kuchroo Lawrence P. Kane Alan J. Korman Arvind Rajpal Sean M. West Minhua Han Christine Bee Xiaodi Deng Xiao Min Schebye Pavel Strop Hassane M. Zarour |
| author_sort | Ornella Pagliano |
| collection | DOAJ |
| description | T cell immunoglobulin mucin domain-containing protein 3 (Tim-3) negatively regulates innate and adaptive immunity in cancer. To identify the mechanisms of Tim-3 in cancer immunity, we evaluated the effects of Tim-3 blockade in human and mouse melanoma. Here, we show that human programmed cell death 1–positive (PD-1+) Tim-3+CD8+ tumor-infiltrating lymphocytes (TILs) upregulate phosphatidylserine (PS), a receptor for Tim-3, and acquire cell surface myeloid markers from antigen-presenting cells (APCs) through transfer of membrane fragments called trogocytosis. Tim-3 blockade acted on Tim-3+ APCs in a PS-dependent fashion to disrupt the trogocytosis of activated tumor antigen–specific CD8+ T cells and PD-1+Tim-3+ CD8+ TILs isolated from patients with melanoma. Tim-3 and PD-1 blockades cooperated to disrupt trogocytosis of CD8+ TILs in 2 melanoma mouse models, decreasing tumor burden and prolonging survival. Deleting Tim-3 in dendritic cells but not in CD8+ T cells impeded the trogocytosis of CD8+ TILs in vivo. Trogocytosed CD8+ T cells presented tumor peptide–major histocompatibility complexes and became the target of fratricide T cell killing, which was reversed by Tim-3 blockade. Our findings have uncovered a mechanism Tim-3 uses to limit antitumor immunity. |
| first_indexed | 2024-12-12T08:33:43Z |
| format | Article |
| id | doaj.art-00341078d5a94f57ba93043742d00efb |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-12-12T08:33:43Z |
| publishDate | 2022-05-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-00341078d5a94f57ba93043742d00efb2022-12-22T00:31:00ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-05-011329Tim-3 mediates T cell trogocytosis to limit antitumor immunityOrnella PaglianoRobert M. MorrisonJoe-Marc ChauvinHridesh BanerjeeDiwakar DavarQuanquan DingTokiyoshi TanegashimaWentao GaoSaranya R. ChakkaRichelle DeBlasioAva LowinKevin KaraMignane KaBochra ZidiRada AminItay RaphaelShuowen ZhangSimon C. WatkinsCindy SanderJohn M. KirkwoodMarcus BosenbergAna C. AndersonVijay K. KuchrooLawrence P. KaneAlan J. KormanArvind RajpalSean M. WestMinhua HanChristine BeeXiaodi DengXiao Min SchebyePavel StropHassane M. ZarourT cell immunoglobulin mucin domain-containing protein 3 (Tim-3) negatively regulates innate and adaptive immunity in cancer. To identify the mechanisms of Tim-3 in cancer immunity, we evaluated the effects of Tim-3 blockade in human and mouse melanoma. Here, we show that human programmed cell death 1–positive (PD-1+) Tim-3+CD8+ tumor-infiltrating lymphocytes (TILs) upregulate phosphatidylserine (PS), a receptor for Tim-3, and acquire cell surface myeloid markers from antigen-presenting cells (APCs) through transfer of membrane fragments called trogocytosis. Tim-3 blockade acted on Tim-3+ APCs in a PS-dependent fashion to disrupt the trogocytosis of activated tumor antigen–specific CD8+ T cells and PD-1+Tim-3+ CD8+ TILs isolated from patients with melanoma. Tim-3 and PD-1 blockades cooperated to disrupt trogocytosis of CD8+ TILs in 2 melanoma mouse models, decreasing tumor burden and prolonging survival. Deleting Tim-3 in dendritic cells but not in CD8+ T cells impeded the trogocytosis of CD8+ TILs in vivo. Trogocytosed CD8+ T cells presented tumor peptide–major histocompatibility complexes and became the target of fratricide T cell killing, which was reversed by Tim-3 blockade. Our findings have uncovered a mechanism Tim-3 uses to limit antitumor immunity.https://doi.org/10.1172/JCI152864ImmunologyOncology |
| spellingShingle | Ornella Pagliano Robert M. Morrison Joe-Marc Chauvin Hridesh Banerjee Diwakar Davar Quanquan Ding Tokiyoshi Tanegashima Wentao Gao Saranya R. Chakka Richelle DeBlasio Ava Lowin Kevin Kara Mignane Ka Bochra Zidi Rada Amin Itay Raphael Shuowen Zhang Simon C. Watkins Cindy Sander John M. Kirkwood Marcus Bosenberg Ana C. Anderson Vijay K. Kuchroo Lawrence P. Kane Alan J. Korman Arvind Rajpal Sean M. West Minhua Han Christine Bee Xiaodi Deng Xiao Min Schebye Pavel Strop Hassane M. Zarour Tim-3 mediates T cell trogocytosis to limit antitumor immunity The Journal of Clinical Investigation Immunology Oncology |
| title | Tim-3 mediates T cell trogocytosis to limit antitumor immunity |
| title_full | Tim-3 mediates T cell trogocytosis to limit antitumor immunity |
| title_fullStr | Tim-3 mediates T cell trogocytosis to limit antitumor immunity |
| title_full_unstemmed | Tim-3 mediates T cell trogocytosis to limit antitumor immunity |
| title_short | Tim-3 mediates T cell trogocytosis to limit antitumor immunity |
| title_sort | tim 3 mediates t cell trogocytosis to limit antitumor immunity |
| topic | Immunology Oncology |
| url | https://doi.org/10.1172/JCI152864 |
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