美国宾夕法尼亚大学Serge Y. Fuchs研究组揭示，ATF3和CH25H调节内源性和免疫治疗性细胞毒性T淋巴细胞(CTLs)的效应吞噬作用和抗肿瘤活性。2022年9月6日出版的《细胞—代谢》杂志发表了这项成果。

他们证明了肿瘤衍生因子 (TDF) 在体外刺激了效应细胞吞噬作用并限制了CTL的肿瘤杀伤活性和活力。TDF有力地改变了CTL的血脂谱，包括消耗 25-羟基胆固醇 (25HC)。25HC抑制吞噬作用并防止CTL失活和自相残杀。从机制上讲，TDFs 诱导 ATF3 转录因子抑制25HC 调节基因——胆固醇25-羟化酶(CH25H)的表达。ATF3-CH25H轴刺激肿瘤内CTL中的吞噬作用减弱了抗肿瘤免疫，刺激了肿瘤生长，并阻碍了嵌合抗原受体(CAR) T细胞过继治疗的功效。通过使用装甲CAR结构或恢复CH25H表达的药物，他们逆转了这些表型并提高了免疫疗法的功效。

研究人员表示，恶性细胞和肿瘤特异性CTLs之间的效应细胞吞噬作用，通过靶细胞上的抗原丢失和其他CTLs对抗原经历的CTLs的自相残杀导致免疫逃避。调节肿瘤中这些事件的机制仍然知之甚少。

附：英文原文

Title: ATF3 and CH25H regulate effector trogocytosis and anti-tumor activities of endogenous and immunotherapeutic cytotoxic T lymphocytes

Author: Zhen Lu, Noreen McBrearty, Jinyun Chen, Vivek S. Tomar, Hongru Zhang, Gianluca De Rosa, Aiwen Tan, Aalim M. Weljie, Daniel P. Beiting, Zhen Miao, Subin S. George, Allison Berger, Gurpanna Saggu, J. Alan Diehl, Constantinos Koumenis, Serge Y. Fuchs

Issue&Volume: 2022/09/06

Abstract: Effector trogocytosis between malignant cells and tumor-specific cytotoxic T lymphocytes(CTLs) contributes to immune evasion through antigen loss on target cells and fratricideof antigen-experienced CTLs by other CTLs. The mechanisms regulating these eventsin tumors remain poorly understood. Here, we demonstrate that tumor-derived factors(TDFs) stimulated effector trogocytosis and restricted CTLs’ tumoricidal activityand viability in vitro. TDFs robustly altered the CTL’s lipid profile, including depletion of 25-hydroxycholesterol(25HC). 25HC inhibited trogocytosis and prevented CTL’s inactivation and fratricide.Mechanistically, TDFs induced ATF3 transcription factor that suppressed the expressionof 25HC-regulating gene—cholesterol 25-hydroxylase (CH25H). Stimulation of trogocytosis in the intratumoral CTL by the ATF3-CH25H axis attenuatedanti-tumor immunity, stimulated tumor growth, and impeded the efficacy of chimericantigen receptor (CAR) T cell adoptive therapy. Through use of armored CAR constructsor pharmacologic agents restoring CH25H expression, we reversed these phenotypes andincreased the efficacy of immunotherapies.

DOI: 10.1016/j.cmet.2022.08.007

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00350-3