上海交通大学邹强等研究人员合作发现，乳酸调节RNA 剪接来促进肿瘤浸润调节性T细胞中CTLA-4的表达。相关论文于2024年2月27日在线发表在《免疫》杂志上。

研究人员证明了乳酸通过CTLA-4调节Foxp3依赖性RNA剪接，以维持肿瘤浸润调节性T（Treg）细胞的表型和功能状态。Treg细胞中的RNA剪接与肿瘤微环境（TME）中的Treg细胞特征相关。泛素特异性肽酶39（USP39）是RNA剪接机器的一个组成部分，它能维持RNA剪接介导的CTLA-4表达，从而控制Treg细胞的功能。从机制上讲，乳酸促进了USP39介导的RNA剪接，从而以Foxp3依赖性方式促进CTLA-4的表达。

此外，在结直肠癌患者的肿瘤浸润Treg细胞中，CTLA-4 RNA剪接的效率也有所提高。这些发现凸显了RNA剪接在Treg细胞中的免疫学意义，并为了解Treg细胞中CTLA-4表达的环境机制提供了重要见解。

据悉，RNA剪接参与了癌症的发生和发展，但它如何在代谢异常的TME中影响宿主的抗肿瘤免疫仍不清楚。

附：英文原文

Title: Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells

Author: Rui Ding, Xiaoyan Yu, Zhilin Hu, Yu Dong, Haiyan Huang, Yuerong Zhang, Qiaoqiao Han, Zhi-Yu Ni, Ren Zhao, Youqiong Ye, Qiang Zou

Issue&Volume: 2024-2-27

Abstract: RNA splicing is involved in cancer initiation and progression, but how it influenceshost antitumor immunity in the metabolically abnormal tumor microenvironment (TME)remains unclear. Here, we demonstrate that lactate modulates Foxp3-dependent RNA splicingto maintain the phenotypic and functional status of tumor-infiltrating regulatoryT (Treg) cells via CTLA-4. RNA splicing in Treg cells was correlated with the Tregcell signatures in the TME. Ubiquitin-specific peptidase 39 (USP39), a component ofthe RNA splicing machinery, maintained RNA-splicing-mediated CTLA-4 expression tocontrol Treg cell function. Mechanistically, lactate promoted USP39-mediated RNA splicingto facilitate CTLA-4 expression in a Foxp3-dependent manner. Moreover, the efficiencyof CTLA-4 RNA splicing was increased in tumor-infiltrating Treg cells from patientswith colorectal cancer. These findings highlight the immunological relevance of RNAsplicing in Treg cells and provide important insights into the environmental mechanismgoverning CTLA-4 expression in Treg cells.

DOI: 10.1016/j.immuni.2024.01.019

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00045-1