Hypoxia Is a Dominant Remodeler of the Effector T Cell Surface Proteome Relative to Activation and Regulatory T Cell Suppression

James R Byrnes; Amy M Weeks; Eric Shifrut; Julia Carnevale; Lisa Kirkemo; Alan Ashworth; Alexander Marson; James A Wells

doi:10.1016/j.mcpro.2022.100217

Hypoxia Is a Dominant Remodeler of the Effector T Cell Surface Proteome Relative to Activation and Regulatory T Cell Suppression

Mol Cell Proteomics. 2022 Apr;21(4):100217. doi: 10.1016/j.mcpro.2022.100217. Epub 2022 Feb 23.

Authors

James R Byrnes¹, Amy M Weeks¹, Eric Shifrut², Julia Carnevale³, Lisa Kirkemo¹, Alan Ashworth⁴, Alexander Marson⁵, James A Wells⁶

Affiliations

¹ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA.
² Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA; Gladstone Institutes, San Francisco, California, USA.
³ Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
⁴ Department of Medicine, University of California, San Francisco, San Francisco, California, USA; The Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
⁵ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA; Gladstone Institutes, San Francisco, California, USA; Department of Medicine, University of California, San Francisco, San Francisco, California, USA; The Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, California, USA; Parker Institute for Cancer Immunotherapy, San Francisco, California, USA; Chan Zuckerberg Biohub, San Francisco, California, USA.
⁶ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA; Chan Zuckerberg Biohub, San Francisco, California, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA. Electronic address: jim.wells@ucsf.edu.

Abstract

Immunosuppressive factors in the tumor microenvironment (TME) impair T cell function and limit the antitumor immune response. T cell surface receptors and surface proteins that influence interactions and function in the TME are proven targets for cancer immunotherapy. However, how the entire surface proteome remodels in primary human T cells in response to specific suppressive factors in the TME remains to be broadly and systematically characterized. Here, using a reductionist cell culture approach with primary human T cells and stable isotopic labeling with amino acids in cell culture-based quantitative cell surface capture glycoproteomics, we examined how two immunosuppressive TME factors, regulatory T cells (Tregs) and hypoxia, globally affect the activated CD8⁺ surface proteome (surfaceome). Surprisingly, coculturing primary CD8⁺ T cells with Tregs only modestly affected the CD8⁺ surfaceome but did partially reverse activation-induced surfaceomic changes. In contrast, hypoxia drastically altered the CD8⁺ surfaceome in a manner consistent with both metabolic reprogramming and induction of an immunosuppressed state. The CD4⁺ T cell surfaceome similarly responded to hypoxia, revealing a common hypoxia-induced surface receptor program. Our surfaceomics findings suggest that hypoxic environments create a challenge for T cell activation. These studies provide global insight into how Tregs and hypoxia remodel the T cell surfaceome and we believe represent a valuable resource to inform future therapeutic efforts to enhance T cell function.

Keywords: T cells; cell surface proteomics; hypoxia; tumor microenvironment.

MeSH terms

CD8-Positive T-Lymphocytes
Humans
Hypoxia
Proteome*
T-Lymphocytes, Regulatory*
Tumor Microenvironment

Substances

Proteome

Abstract

MeSH terms

Substances

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