Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors

Shihao Xu; Omkar Chaudhary; Patricia Rodríguez-Morales; Xiaoli Sun; Dan Chen; Roberta Zappasodi; Ziyan Xu; Antonio F M Pinto; April Williams; Isabell Schulze; Yagmur Farsakoglu; Siva Karthik Varanasi; Jun Siong Low; Wenxi Tang; Haiping Wang; Bryan McDonald; Victoria Tripple; Michael Downes; Ronald M Evans; Nada A Abumrad; Taha Merghoub; Jedd D Wolchok; Maxim N Shokhirev; Ping-Chih Ho; Joseph L Witztum; Brinda Emu; Guoliang Cui; Susan M Kaech

doi:10.1016/j.immuni.2021.05.003

Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8⁺ T cells in tumors

Immunity. 2021 Jul 13;54(7):1561-1577.e7. doi: 10.1016/j.immuni.2021.05.003. Epub 2021 Jun 7.

Authors

Shihao Xu¹, Omkar Chaudhary², Patricia Rodríguez-Morales¹, Xiaoli Sun³, Dan Chen¹, Roberta Zappasodi⁴, Ziyan Xu⁵, Antonio F M Pinto⁶, April Williams⁷, Isabell Schulze⁴, Yagmur Farsakoglu¹, Siva Karthik Varanasi¹, Jun Siong Low⁸, Wenxi Tang³, Haiping Wang⁹, Bryan McDonald¹, Victoria Tripple¹, Michael Downes¹⁰, Ronald M Evans¹⁰, Nada A Abumrad¹¹, Taha Merghoub¹², Jedd D Wolchok¹², Maxim N Shokhirev⁷, Ping-Chih Ho⁹, Joseph L Witztum³, Brinda Emu², Guoliang Cui¹³, Susan M Kaech¹⁴

Affiliations

¹ NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
² Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06510, USA.
³ Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
⁴ Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
⁵ NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.
⁶ Mass Spectrometry Core for Proteomics and Metabolomics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁷ The Razavi Newman Integrative Genomics and Bioinformatics Core Facility, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁸ Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA; Fondazione per l'istituto di ricerca in biomedicina, Bellinzona, Switzerland.
⁹ Department of Fundamental Oncology, Ludwig Institute for Cancer Research at University of Lausanne, Lausanne, Switzerland.
¹⁰ Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
¹¹ Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹² Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹³ T Cell Metabolism Group (D140), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany. Electronic address: [email protected].
¹⁴ NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: [email protected].

Abstract

A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8⁺ tumor infiltrating lymphocytes (TILs) respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8⁺ TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8⁺ TILs, which also correlated with progressive T cell dysfunction. Cd36^-/- T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8⁺ TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8⁺ T cell dysfunction and serves as a therapeutic avenue for immunotherapies.

Keywords: CD36; CD8(+) T cells; lipid peroxidation; oxidized lipids; tumor microenvironment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biological Transport / physiology
CD36 Antigens / metabolism*
CD8-Positive T-Lymphocytes / metabolism*
Cell Line, Tumor
HEK293 Cells
Humans
Leukocytes, Mononuclear / metabolism
Lipid Peroxidation / physiology*
Lipoproteins, LDL / metabolism*
Lymphocytes, Tumor-Infiltrating / metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neoplasms / metabolism*
Receptors, Scavenger / metabolism*
Tumor Microenvironment / physiology

Substances

CD36 Antigens
Lipoproteins, LDL
Receptors, Scavenger
oxidized low density lipoprotein

Abstract

Publication types

MeSH terms

Substances

Grants and funding