CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4

Peng Liao; Weimin Wang; Weichao Wang; Ilona Kryczek; Xiong Li; Yingjie Bian; Amanda Sell; Shuang Wei; Sara Grove; Jeffrey K Johnson; Paul D Kennedy; Miguel Gijón; Yatrik M Shah; Weiping Zou

doi:10.1016/j.ccell.2022.02.003

CD8⁺ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4

Cancer Cell. 2022 Apr 11;40(4):365-378.e6. doi: 10.1016/j.ccell.2022.02.003. Epub 2022 Feb 24.

Authors

Affiliations

¹ Department of Surgery, University of Michigan School of Medicine, BSRB, 109 Zina Pitcher Place, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
² Cayman Chemical Company, Ann Arbor, MI, USA.
³ Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
⁴ Department of Surgery, University of Michigan School of Medicine, BSRB, 109 Zina Pitcher Place, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA; Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Graduate Program in Tumor Biology, University of Michigan School of Medicine, Ann Arbor, MI, USA. Electronic address: wzou@med.umich.edu.

Abstract

Tumor cell intrinsic ferroptosis-initiating mechanisms are unknown. Here, we discover that T cell-derived interferon (IFN)γ in combination with arachidonic acid (AA) induces immunogenic tumor ferroptosis, serving as a mode of action for CD8⁺ T cell (CTL)-mediated tumor killing. Mechanistically, IFNγ stimulates ACSL4 and alters tumor cell lipid pattern, thereby increasing incorporations of AA into C16 and C18 acyl chain-containing phospholipids. Palmitoleic acid and oleic acid, two common C16 and C18 fatty acids in blood, promote ACSL4-dependent tumor ferroptosis induced by IFNγ plus AA. Moreover, tumor ACSL4 deficiency accelerates tumor progression. Low-dose AA enhances tumor ferroptosis and elevates spontaneous and immune checkpoint blockade (ICB)-induced anti-tumor immunity. Clinically, tumor ACSL4 correlates with T cell signatures and improved survival in ICB-treated cancer patients. Thus, IFNγ signaling paired with selective fatty acids is a natural tumor ferroptosis-promoting mechanism and a mode of action of CTLs. Targeting the ACSL4 pathway is a potential anti-cancer approach.

Keywords: ACSL4; PD-L1; T cell; arachidonic acid; cancer; ferroptosis; immunotherapy; interferon; oleic acid; palmitoleic acid.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

CD8-Positive T-Lymphocytes / metabolism
Coenzyme A Ligases / metabolism
Fatty Acids
Ferroptosis*
Humans
Neoplasms*

Substances

Fatty Acids
Coenzyme A Ligases

Abstract

Publication types

MeSH terms

Substances

Grants and funding