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

被引：584

作者：

Liao, Peng ^{[1
,2
]}

Wang, Weimin ^{[1
,2
]}

Wang, Weichao ^{[1
,2
]}

Kryczek, Ilona ^{[1
,2
]}

Li, Xiong ^{[1
,2
]}

Bian, Yingjie ^{[1
,2
]}

Sell, Amanda ^{[1
,2
]}

Wei, Shuang ^{[1
,2
]}

Grove, Sara ^{[1
,2
]}

Johnson, Jeffrey K. ^{[3
]}

Kennedy, Paul D. ^{[3
]}

Gijon, Miguel ^{[3
]}

Shah, Yatrik M. ^{[4
]}

Zou, Weiping ^{[1
,2
,5
,6
,7
]}

机构：

[1] Univ Michigan, Sch Med, Dept Surg, BSRB, 109 Zina Pitcher Pl, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Ctr Excellence Canc Immunol & Immunotherapy, Rogel Canc Ctr, Sch Med, Ann Arbor, MI 48109 USA

[3] Cayman Chem Co, Ann Arbor, MI USA

[4] Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI USA

[5] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA

[6] Univ Michigan, Grad Program Immunol, Sch Med, Ann Arbor, MI 48109 USA

[7] Univ Michigan, Grad Program Tumor Biol, Sch Med, Ann Arbor, MI 48109 USA

来源：

CANCER CELL | 2022年 / 40卷 / 04期

关键词：

ROLES; PEROXIDATION; INFLAMMATION; CYTOKINE; BIOLOGY; GROWTH; GAMMA;

D O I：

10.1016/j.ccell.2022.02.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Tumor cell intrinsic ferroptosis-initiating mechanisms are unknown. Here, we discover that T cell-derived interferon (IFN)gamma 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, IFN gamma 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 IFN gamma 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, IFN gamma 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.

引用

页码：365 / +

页数：20

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