Fucosylation of HLA-DRB1 regulates CD4+ T cell-mediated anti-melanoma immunity and enhances immunotherapy efficacy
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Published:2023-01-23
Issue:2
Volume:4
Page:222-239
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ISSN:2662-1347
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Container-title:Nature Cancer
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language:en
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Short-container-title:Nat Cancer
Author:
Lester Daniel K., Burton Chase, Gardner AlyciaORCID, Innamarato Patrick, Kodumudi Krithika, Liu Qian, Adhikari Emma, Ming Qianqian, Williamson Daniel B., Frederick Dennie T.ORCID, Sharova Tatyana, White Michael G.ORCID, Markowitz Joseph, Cao Biwei, Nguyen JonathanORCID, Johnson Joseph, Beatty Matthew, Mockabee-Macias Andrea, Mercurio Matthew, Watson Gregory, Chen Pei-Ling, McCarthy Susan, MoranSegura CarlosORCID, Messina Jane, Thomas Kerry L., Darville Lancia, Izumi Victoria, Koomen John M.ORCID, Pilon-Thomas Shari A., Ruffell BrianORCID, Luca Vincent C., Haltiwanger Robert S.ORCID, Wang XuefengORCID, Wargo Jennifer A.ORCID, Boland Genevieve M.ORCID, Lau Eric K.ORCID
Abstract
AbstractImmunotherapy efficacy is limited in melanoma, and combinations of immunotherapies with other modalities have yielded limited improvements but also adverse events requiring cessation of treatment. In addition to ineffective patient stratification, efficacy is impaired by paucity of intratumoral immune cells (itICs); thus, effective strategies to safely increase itICs are needed. We report that dietary administration of l-fucose induces fucosylation and cell surface enrichment of the major histocompatibility complex (MHC)-II protein HLA-DRB1 in melanoma cells, triggering CD4+ T cell-mediated increases in itICs and anti-tumor immunity, enhancing immune checkpoint blockade responses. Melanoma fucosylation and fucosylated HLA-DRB1 associate with intratumoral T cell abundance and anti-programmed cell death protein 1 (PD1) responder status in patient melanoma specimens, suggesting the potential use of melanoma fucosylation as a strategy for stratifying patients for immunotherapies. Our findings demonstrate that fucosylation is a key mediator of anti-tumor immunity and, importantly, suggest that l-fucose is a powerful agent for safely increasing itICs and immunotherapy efficacy in melanoma.
Funder
U.S. Department of Health & Human Services | NIH | National Cancer Institute Harry J. Lloyd Charitable Trust U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology
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