SCI 29 May 2023

Conserved transcriptional connectivity of regulatory T cells in the tumor microenvironment informs new combination cancer therapy strategies

（nature immunology；IF: 31.25）

Ariella Glasner, Samuel A. Rose, Roshan Sharma, Herman Gudjonson, Tinyi Chu, Jesse A. Green, Sham Rampersaud, Izabella K. Valdez, Emma S. Andretta, Bahawar S. Dhillon, Michail Schizas, Stanislav Dikiy, Alejandra Mendoza, Wei Hu, Zhong-Min Wang, Ojasvi Chaudhary, Tianhao Xu, Linas Mazutis, Gabrielle Rizzuto, Alvaro Quintanal-Villalonga, Parvathy Manoj, Elisa de Stanchina, Charles M. Rudin, Dana Pe’er & Alexander Y. Rudensky

CORRESPONDENCE TO: peerd@mskcc.org; rudenska@mskcc.org 

While regulatory T (Treg) cells are traditionally viewed as professional suppressors of antigen presenting cells and effector T cells in both autoimmunity and cancer, recent findings of distinct Treg cell functions in tissue maintenance suggest that their regulatory purview extends to a wider range of cells and is broader than previously assumed. To elucidate tumoral Treg cell ‘connectivity’ to diverse tumor-supporting accessory cell types, we explored immediate early changes in their single-cell transcriptomes upon punctual Treg cell depletion in experimental lung cancer and injury-induced inflammation. Before any notable T cell activation and inflammation, fibroblasts, endothelial and myeloid cells exhibited pronounced changes in their gene expression in both cancer and injury settings. Factor analysis revealed shared Treg cell-dependent gene programs, foremost, prominent upregulation of VEGF and CCR2 signaling-related genes upon Treg cell deprivation in either setting, as well as in Treg cell-poor versus Treg cell-rich human lung adenocarcinomas. Accordingly, punctual Treg cell depletion combined with short-term VEGF blockade showed markedly improved control of PD-1 blockade-resistant lung adenocarcinoma progression in mice compared to the corresponding monotherapies, highlighting a promising factor-based querying approach to elucidating new rational combination treatments of solid organ cancers. 

虽然调节性T(Treg)细胞在传统上被视为自身免疫和癌症中抗原呈递细胞和效应T细胞的专业抑制者，但最近关于组织维护中不同Treg细胞功能的发现表明，它们的调节范围延伸到更多的细胞，而且比以前假设的更广泛。为了阐明肿瘤Treg细胞与各种支持肿瘤的附属细胞类型的关系，我们探讨了在实验性肺癌和损伤诱导的炎症中，当Treg细胞被准时耗尽时，其单细胞转录组的直接早期变化。在任何明显的T细胞激活和炎症之前，成纤维细胞、内皮细胞和骨髓细胞在癌症和损伤环境中的基因表达都表现出明显的变化。因子分析显示了共同的Treg细胞依赖性基因程序，最重要的是，在两种情况下，Treg细胞缺乏与Treg细胞丰富的人类肺腺癌中，当Treg细胞被剥夺时，VEGF和CCR2信号相关的基因明显上调。因此，与相应的单一疗法相比，准时剥夺Treg细胞与短期VEGF阻断相结合，明显改善了对PD-1阻断剂小鼠肺腺癌进展的控制，突出了一种有希望的基于因素的查询方法，以阐明新的实体瘤的合理组合治疗。

来源 | 健康界

版权归原作者所有，若有违规、侵权请联系我们