TY - JOUR
T1 - Fucosylation of HLA-DRB1 regulates CD4+ T cell-mediated anti-melanoma immunity and enhances immunotherapy efficacy
AU - Lester, Daniel K.
AU - Burton, Chase
AU - Gardner, Alycia
AU - Innamarato, Patrick
AU - Kodumudi, Krithika
AU - Liu, Qian
AU - Adhikari, Emma
AU - Ming, Qianqian
AU - Williamson, Daniel B.
AU - Frederick, Dennie T.
AU - Sharova, Tatyana
AU - White, Michael G.
AU - Markowitz, Joseph
AU - Cao, Biwei
AU - Nguyen, Jonathan
AU - Johnson, Joseph
AU - Beatty, Matthew
AU - Mockabee-Macias, Andrea
AU - Mercurio, Matthew
AU - Watson, Gregory
AU - Chen, Pei Ling
AU - McCarthy, Susan
AU - MoranSegura, Carlos
AU - Messina, Jane
AU - Thomas, Kerry L.
AU - Darville, Lancia
AU - Izumi, Victoria
AU - Koomen, John M.
AU - Pilon-Thomas, Shari A.
AU - Ruffell, Brian
AU - Luca, Vincent C.
AU - Haltiwanger, Robert S.
AU - Wang, Xuefeng
AU - Wargo, Jennifer A.
AU - Boland, Genevieve M.
AU - Lau, Eric K.
N1 - Funding Information:
We are grateful to all Lau laboratory members and to S. Chellappan, J. Cleveland, J. Conéjo-Garcia, G. DeNicola, F. Karreth, A. Gomes and D. Abate-Daga at the Moffitt Cancer Center for critical readings of the manuscript. We also thank Z. Ronai for his mentorship, as well as Michiko Fukuda, Minoru Fukuda and H. Freeze for their technical advice and guidance in glycobiological studies. We acknowledge E. Sahakian for technical assistance and advice and M. Meister, T. Alvarez and T. Christie for administrative support. This work has been supported in part by the Moffitt/USF Vivarium, Flow Cytometry Core, Biostatistics and Bioinformatics Shared Resource, Analytical Microscopy, Tissue Core and Proteomics and Metabolomics Core Facilities (we thank in particular N. Clark and J. Balasi for technical Tissue Core support and B. Fang for proteomic repository assistance) and the Advanced Analytical and Digital Laboratory at the H. Lee Moffitt Cancer Center and Research Institute, an NCI-designated Comprehensive Cancer Center (P30-CA076292). We acknowledge the Proteomic Shared Resource of the Sanford Burnham Prebys Medical Discovery Institute for their assistance with fucosylated proteomic screening. Support from an NIGMS grant (GM061126 to R.S.H.), an NCI grant (KO8CA252164 to J.M.), NCI grants (K99CA172705, R00CA172705 and R01CA241559 to E.K.L.), a Miles for Moffitt grant (to E.K.L.) and a Harry J. Lloyd Charitable Trust Melanoma Research grant (to E.K.L.) are gratefully acknowledged.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/2
Y1 - 2023/2
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85146681828&partnerID=8YFLogxK
U2 - 10.1038/s43018-022-00506-7
DO - 10.1038/s43018-022-00506-7
M3 - Article
C2 - 36690875
AN - SCOPUS:85146681828
SN - 2662-1347
VL - 4
SP - 222
EP - 239
JO - Nature Cancer
JF - Nature Cancer
IS - 2
ER -