CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors

Depleting regulatory T cells (T reg 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 approac...

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Vydané v:	Nature immunology Ročník 21; číslo 3; s. 298 - 308
Hlavní autori:	Wang, Haiping, Franco, Fabien, Tsui, Yao-Chen, Xie, Xin, Trefny, Marcel P., Zappasodi, Roberta, Mohmood, Syed Raza, Fernández-García, Juan, Tsai, Chin-Hsien, Schulze, Isabell, Picard, Florence, Meylan, Etienne, Silverstein, Roy, Goldberg, Ira, Fendt, Sarah-Maria, Wolchok, Jedd D., Merghoub, Taha, Jandus, Camilla, Zippelius, Alfred, Ho, Ping-Chih
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	New York Nature Publishing Group US 01.03.2020 Nature Publishing Group
Predmet:	631/250/2152 631/67/580 Adaptation Animals Antitumor activity Apoptosis Apoptosis - immunology Autoimmunity Biomedical and Life Sciences Biomedicine Cancer immunotherapy CD36 antigen CD36 Antigens - deficiency CD36 Antigens - genetics CD36 Antigens - immunology Cell death Cell Line, Tumor Cell metabolism Cell survival Fatty acids Female Genetic aspects Genetic regulation Health aspects Homeostasis Homeostasis - immunology Humans Immunology Immunoregulation Immunotherapy Infectious Diseases Lactic acid Lipid Metabolism - genetics Lymphocytes Lymphocytes T Lymphocytes, Tumor-Infiltrating - immunology Male Metabolism Mice Mice, Inbred C57BL Mice, Knockout Mitochondria Neoplasms - immunology Neoplasms - metabolism Neoplasms - pathology PPAR-beta - immunology Signal Transduction - immunology T cells T-Lymphocytes, Regulatory - immunology T-Lymphocytes, Regulatory - metabolism T-Lymphocytes, Regulatory - pathology Tumor microenvironment Tumor Microenvironment - immunology Tumor-infiltrating lymphocytes Tumors Switzerland
ISSN:	1529-2908, 1529-2916, 1529-2916
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Shrnutí:	Depleting regulatory T cells (T reg 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 T reg cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral T reg cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via peroxisome proliferator-activated receptor-β signaling, programming T reg cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in T reg cells suppressed tumor growth accompanied by a decrease in intratumoral T reg 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 T reg cells, and the therapeutic potential of targeting this pathway for reprogramming the TME. Tumor environments are highly acidic due to high concentrations of lactic acid. Ho and colleagues report that tumor-infiltrating regulatory T cells adapt to this tumor environment by upregulating expression of CD36, which allows them to use fatty acids to fuel their metabolism.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1529-2908 1529-2916 1529-2916
DOI:	10.1038/s41590-019-0589-5