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美国哥伦比亚大学欧文医学中心Andrea Califano课题组报道了肿瘤浸润调节性T细胞(TI-Tregs)主调控因子的系统阐释和药理靶向。该项研究成果发表在2023年4月27日出版的《癌细胞》上。

由于其免疫抑制作用，TI-Treg代表了有吸引力的免疫肿瘤学靶点。研究人员对来自4种恶性肿瘤的36例患者的TI与外周血Tregs (P-Tregs)的分析，确定了17个候选主调控因子(MRs)作为TI-Treg转录状态的机制决定因素。使用嵌合造血干细胞移植模型在体内进行CRISPR- Cas9筛选，研究人员证实了8个MRs在TI-Treg募集和/或保留中的重要性，而不影响其他T细胞亚型，并且通过CRISPR KO靶向最重要的MRs之一(Trps1)可显著降低异位肿瘤的生长。

通过对能够逆转TI-Treg MR活性的药物进行分析，研究人员确定低剂量吉西他滨为最佳预测。事实上，吉西他滨治疗抑制了免疫功能正常而非免疫功能低下的同种异体移植物的肿瘤生长，增加了抗PD-1的疗效，并在体内减少了MR表达的TI-Tregs。该研究提供了Treg信号传导的关键见解，特别是在癌症背景下，以及系统阐明和靶向免疫抑制亚群中的MR蛋白的可推广策略。

附：英文原文

Title: Systematic elucidation and pharmacological targeting of tumor-infiltrating regulatory T cell master regulators

Author: Aleksandar Obradovic, Casey Ager, Mikko Turunen, Thomas Nirschl, Mohsen Khosravi-Maharlooei, Alina Iuga, Christopher M. Jackson, Srinivasan Yegnasubramanian, Lorenzo Tomassoni, Ester Calvo Fernandez, Patrick McCann, Meri Rogava, Angelo M. DeMarzo, Christina M. Kochel, Mohamad Allaf, Trinity Bivalacqua, Michael Lim, Ronald Realubit, Charles Karan, Charles G. Drake, Andrea Califano

Issue&Volume: 2023-04-27

Abstract: Due to their immunosuppressive role, tumor-infiltrating regulatory T cells (TI-Tregs)represent attractive immuno-oncology targets. Analysis of TI vs. peripheral Tregs(P-Tregs) from 36 patients, across four malignancies, identified 17 candidate masterregulators (MRs) as mechanistic determinants of TI-Treg transcriptional state. PooledCRISPR-Cas9 screening in vivo, using a chimeric hematopoietic stem cell transplant model, confirmed the essentialityof eight MRs in TI-Treg recruitment and/or retention without affecting other T cellsubtypes, and targeting one of the most significant MRs (Trps1) by CRISPR KO significantlyreduced ectopic tumor growth. Analysis of drugs capable of inverting TI-Treg MR activityidentified low-dose gemcitabine as the top prediction. Indeed, gemcitabine treatmentinhibited tumor growth in immunocompetent but not immunocompromised allografts, increasedanti-PD-1 efficacy, and depleted MR-expressing TI-Tregs in vivo. This study provides key insight into Treg signaling, specifically in the contextof cancer, and a generalizable strategy to systematically elucidate and target MRproteins in immunosuppressive subpopulations.

DOI: 10.1016/j.ccell.2023.04.003

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00129-0

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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