Fucosylation of HLA-DRB1 regulates CD4+ T cell-mediated anti-melanoma immunity and enhances immunotherapy efficacy
Daniel Lester, Chase Burton, Alycia Gardner, Patrick Innamarato, Krithika N. Kodumudi, Qian Liu, Emma Adhikari, Qianqian Ming, Daniel B. Williamson, Dennie T. Frederick, Tatyana Sharova, Michael G. White, Joseph Markowitz, Biwei Cao, Jonathan V. Nguyen, Joseph Johnson, Matthew Beatty, Andrea Mockabee‐Macias, Matthew Mercurio, G. Watson, Pei-Ling Chen, Susan McCarthy, Carlos Moran Segura, Jane L. Messina, Kerry Thomas, Lancia Darville, Victoria Izumi, John M. Koomen, Shari Pilon‐Thomas, Brian Ruffell, Vincent C. Luca, Robert S. Haltiwanger, Xuefeng Wang, Jennifer A. Wargo, Genevieve M. Boland, Eric K. Lau
Abstract
Abstract Immunotherapy 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.