Autophagy Regulation of Metabolism Is Required for CD8+ T Cell Anti-tumor Immunity

Lindsay DeVorkin; Nils Pavey; Gillian Carleton; Alexandra Comber; Cally Ho; Junghyun Lim; Erin McNamara; Haochu Huang; Paul Kim; Lauren G Zacharias; Noboru Mizushima; Tatsuya Saitoh; Shizuo Akira; Wayne Beckham; Alireza Lorzadeh; Michelle Moksa; Qi Cao; Aditya Murthy; Martin Hirst; Ralph J DeBerardinis; Julian J Lum

doi:10.1016/j.celrep.2019.03.037

Autophagy Regulation of Metabolism Is Required for CD8⁺ T Cell Anti-tumor Immunity

Cell Rep. 2019 Apr 9;27(2):502-513.e5. doi: 10.1016/j.celrep.2019.03.037.

Authors

Lindsay DeVorkin¹, Nils Pavey¹, Gillian Carleton², Alexandra Comber¹, Cally Ho², Junghyun Lim³, Erin McNamara⁴, Haochu Huang⁴, Paul Kim², Lauren G Zacharias⁵, Noboru Mizushima⁶, Tatsuya Saitoh⁷, Shizuo Akira⁸, Wayne Beckham⁹, Alireza Lorzadeh¹⁰, Michelle Moksa¹⁰, Qi Cao¹⁰, Aditya Murthy³, Martin Hirst¹¹, Ralph J DeBerardinis¹², Julian J Lum¹³

Affiliations

¹ Trev and Joyce Deeley Research Centre, BC Cancer, Victoria, BC, Canada.
² Trev and Joyce Deeley Research Centre, BC Cancer, Victoria, BC, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada.
³ Department of Cancer Immunology, Genentech, Inc., South San Francisco, CA, USA.
⁴ Department of In Vivo Pharmacology, Genentech, Inc., South San Francisco, CA, USA.
⁵ Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁶ Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
⁷ Division of Inflammation Biology, Institute for Enzyme Research, Tokushima University, Tokushima, Japan.
⁸ Department of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
⁹ BC Cancer-Vancouver Island Centre, Medical Physics, Victoria, BC, Canada; Department of Physics and Astronomy, University of Victoria, Victoria, BC, Canada.
¹⁰ Department of Microbiology and Immunology and Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.
¹¹ Department of Microbiology and Immunology and Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada; Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, Canada.
¹² Children's Medical Center Research Institute, Department of Pediatrics and McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹³ Trev and Joyce Deeley Research Centre, BC Cancer, Victoria, BC, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada. Electronic address: [email protected].

PMID: 30970253
DOI: 10.1016/j.celrep.2019.03.037

Abstract

Autophagy is a cell survival process essential for the regulation of immune responses to infections. However, the role of T cell autophagy in anti-tumor immunity is less clear. Here, we demonstrate a cell-autonomous role for autophagy in the regulation of CD8⁺ T-cell-mediated control of tumors. Mice deficient for the essential autophagy genes Atg5, Atg14, or Atg16L1 display a dramatic impairment in the growth of syngeneic tumors. Moreover, T cells lacking Atg5 have a profound shift to an effector memory phenotype and produce greater amounts of interferon-γ (IFN-γ) and tumor necrosis factor α (TNF-α). Mechanistically, Atg5^-/- CD8⁺ T cells exhibit enhanced glucose metabolism that results in alterations in histone methylation, increases in H3K4me3 density, and transcriptional upregulation of both metabolic and effector target genes. Nonetheless, glucose restriction is sufficient to suppress Atg5-dependent increases in effector function. Thus, autophagy-dependent changes in CD8⁺ T cell metabolism directly regulate anti-tumor immunity.

Keywords: CD8(+) T cells; SAM; anti-tumor immunity; autophagy; glycolysis; lactate; methylation.

Publication types

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

MeSH terms

Animals
Autophagy
CD8-Positive T-Lymphocytes / immunology*
Humans
Mice
Neoplasms / immunology*

Grants and funding

HHMI/Howard Hughes Medical Institute/United States