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

Autor: Haiping Wang, Taha Merghoub, Sarah-Maria Fendt, Camilla Jandus, Ping-Chih Ho, Xin Xie, Fabien Franco, Juan Fernández-García, Etienne Meylan, Ira Goldberg, Chin Hsien Tsai, Yao Chen Tsui, Isabell Schulze, Roy L. Silverstein, Roberta Zappasodi, Jedd D. Wolchok, Marcel P. Trefny, Alfred Zippelius, Florence Picard, Syed Raza Mohmood
Rok vydání: 2019
Předmět:
0301 basic medicine
CD36 Antigens
Male
FITNESS
muscle
medicine.medical_treatment
Apoptosis
medicine.disease_cause
THERAPY
T-Lymphocytes
Regulatory
Autoimmunity
Mice
0302 clinical medicine
Cancer immunotherapy
Neoplasms
foxp3
Tumor Microenvironment
Immunology and Allergy
Homeostasis
Mice
Knockout
depletion
hemic and immune systems
MUSCLE
fitness
medicine.anatomical_structure
Female
Immunotherapy
DEPLETION
Life Sciences & Biomedicine
Reprogramming
Signal Transduction
FOXP3
Regulatory T cell
REPROGRAMS
Immunology
chemical and pharmacologic phenomena
macrophage
Biology
03 medical and health sciences
Lymphocytes
Tumor-Infiltrating
Downregulation and upregulation
Cell Line
Tumor
medicine
Animals
Apoptosis/immunology
CD36 Antigens/deficiency
CD36 Antigens/genetics
CD36 Antigens/immunology
Homeostasis/immunology
Humans
Lipid Metabolism/genetics
Lymphocytes
Tumor-Infiltrating/immunology
Mice
Inbred C57BL
Neoplasms/immunology
Neoplasms/metabolism
Neoplasms/pathology
PPAR-beta/immunology
Signal Transduction/immunology
T-Lymphocytes
Regulatory/immunology
T-Lymphocytes
Regulatory/metabolism
T-Lymphocytes
Regulatory/pathology
Tumor Microenvironment/immunology
PPAR-beta
therapy
Tumor microenvironment
Science & Technology
tregs
Lipid Metabolism
reprograms
030104 developmental biology
Cell culture
Cancer research
MACROPHAGE
TREGS
030215 immunology
Zdroj: Nature immunology, vol. 21, no. 3, pp. 298-308
Nature Immunology, Vol. 21, No 3 (2020) pp. 298-308
Nature Immunology
ISSN: 1529-2916
1529-2908
Popis: 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-beta 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.
Databáze: OpenAIRE
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