CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors Journal Article
| Authors: | Wang, H.; Franco, F.; Tsui, Y. C.; Xie, X.; Trefny, M. P.; Zappasodi, R.; Mohmood, S. R.; Fernández-García, J.; Tsai, C. H.; Schulze, I.; Picard, F.; Meylan, E.; Silverstein, R.; Goldberg, I.; Fendt, S. M.; Wolchok, J. D.; Merghoub, T.; Jandus, C.; Zippelius, A.; Ho, P. C. |
| Article Title: | CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors |
| Abstract: | Depleting regulatory T cells (Treg cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral Treg cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral Treg cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via peroxisome proliferator-activated receptor-β signaling, programming Treg cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in Treg cells suppressed tumor growth accompanied by a decrease in intratumoral Treg cells and enhancement of antitumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive antitumor responses with anti-programmed cell death protein 1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrates the survival and functions of intratumoral Treg cells, and the therapeutic potential of targeting this pathway for reprogramming the TME. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. |
| Keywords: | signal transduction; controlled study; nonhuman; neoplasm; tumor associated leukocyte; animal cell; mouse; animal tissue; cell survival; cancer immunotherapy; melanoma; apoptosis; gene expression; animal experiment; animal model; in vivo study; caspase 3; antineoplastic activity; cancer inhibition; regulatory t lymphocyte; upregulation; fitness; homeostasis; ex vivo study; lipid metabolism; antibody; lymphocyte function; nuclear reprogramming; lactic acid; cd36 antigen; adaptation; priority journal; article; peroxisome proliferator activated receptor delta |
| Journal Title: | Nature Immunology |
| Volume: | 21 |
| Issue: | 3 |
| ISSN: | 1529-2908 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2020-03-01 |
| Start Page: | 298 |
| End Page: | 308 |
| Language: | English |
| DOI: | 10.1038/s41590-019-0589-5 |
| PUBMED: | 32066953 |
| PROVIDER: | scopus |
| PMCID: | PMC7043937 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 April 2020 -- Source: Scopus |
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