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CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4.
Liao, Peng; Wang, Weimin; Wang, Weichao; Kryczek, Ilona; Li, Xiong; Bian, Yingjie; Sell, Amanda; Wei, Shuang; Grove, Sara; Johnson, Jeffrey K; Kennedy, Paul D; Gijón, Miguel; Shah, Yatrik M; Zou, Weiping.
Affiliation
  • Liao P; 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.
  • Wang W; 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.
  • Wang W; 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.
  • Kryczek I; 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.
  • Li X; 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.
  • Bian Y; 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.
  • Sell A; 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.
  • Wei S; 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.
  • Grove S; 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.
  • Johnson JK; Cayman Chemical Company, Ann Arbor, MI, USA.
  • Kennedy PD; Cayman Chemical Company, Ann Arbor, MI, USA.
  • Gijón M; Cayman Chemical Company, Ann Arbor, MI, USA.
  • Shah YM; Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
  • Zou W; 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
Cancer Cell ; 40(4): 365-378.e6, 2022 04 11.
Article in En | MEDLINE | ID: mdl-35216678
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ferroptosis / Neoplasms Limits: Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2022 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ferroptosis / Neoplasms Limits: Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2022 Document type: Article Affiliation country: United States