Dietary elaidic acid boosts tumoral antigen presentation and cancer immunity via ACSL5.

Cell metabolism Pub Date : 2024-04-02 Epub Date: 2024-02-12 DOI:10.1016/j.cmet.2024.01.012
Yongfeng Lai, Yuan Gao, Junhong Lin, Fangfang Liu, Liguo Yang, Jie Zhou, Ying Xue, Yan Li, Zhenzhen Chang, Jing Li, Tengfei Chao, Jing Chen, Xiang Cheng, Xianfu Gao, Xiong Li, Fujia Lu, Qian Chu, Weimin Wang
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Abstract

Immunomodulatory effects of long-chain fatty acids (LCFAs) and their activating enzyme, acyl-coenzyme A (CoA) synthetase long-chain family (ACSL), in the tumor microenvironment remain largely unknown. Here, we find that ACSL5 functions as an immune-dependent tumor suppressor. ACSL5 expression sensitizes tumors to PD-1 blockade therapy in vivo and the cytotoxicity mediated by CD8+ T cells in vitro via regulation of major histocompatibility complex class I (MHC-I)-mediated antigen presentation. Through screening potential substrates for ACSL5, we further identify that elaidic acid (EA), a trans LCFA that has long been considered harmful to human health, phenocopies to enhance MHC-I expression. EA supplementation can suppress tumor growth and sensitize PD-1 blockade therapy. Clinically, ACSL5 expression is positively associated with improved survival in patients with lung cancer, and plasma EA level is also predictive for immunotherapy efficiency. Our findings provide a foundation for enhancing immunotherapy through either targeting ACSL5 or metabolic reprogramming of antigen presentation via dietary EA supplementation.

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膳食中的麦饭石酸可通过 ACSL5 促进肿瘤抗原呈递和癌症免疫。
长链脂肪酸(LCFAs)及其激活酶--酰基辅酶A(CoA)合成酶长链家族(ACSL)--在肿瘤微环境中的免疫调节作用在很大程度上仍不为人所知。在这里,我们发现 ACSL5 具有免疫依赖性肿瘤抑制因子的功能。通过调节主要组织相容性复合体 I 类(MHC-I)介导的抗原递呈,ACSL5 的表达使肿瘤对体内的 PD-1 阻断疗法和体外 CD8+ T 细胞介导的细胞毒性敏感。通过筛选 ACSL5 的潜在底物,我们进一步发现,一直被认为对人类健康有害的反式低脂脂肪酸麦饭石酸(EA)具有增强 MHC-I 表达的表型。补充 EA 可抑制肿瘤生长并使 PD-1 阻断疗法敏感。在临床上,ACSL5的表达与肺癌患者生存率的提高呈正相关,血浆EA水平还能预测免疫疗法的效率。我们的研究结果为通过膳食补充 EA 靶向 ACSL5 或对抗原呈递进行代谢重编程来增强免疫疗法奠定了基础。
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