Title Conserved transcriptional connectivity of regulatory T cells in the tumor microenvironment informs new combination cancer therapy strategies /
Authors Glasner, Ariella ; Rose, Samuel A ; Sharma, Roshan ; Gudjonson, Herman ; Chu, Tinyi ; Green, Jesse A ; Rampersaud, Sham ; Valdez, Izabella K ; Andretta, Emma S ; Dhillon, Bahawar S ; Schizas, Michail ; Dikiy, Stanislav ; Mendoza, Alejandra ; Hu, Wei ; Wang, Zhong-Min ; Chaudhary, Ojasvi ; Xu, Tianhao ; Mažutis, Linas ; Rizzuto, Gabrielle ; Quintanal-Villalonga, Alvaro ; Manoj, Parvathy ; de Stanchina, Elisa ; Rudin, Charles M ; Pe'er, Dana ; Rudensky, Alexander Y
DOI 10.1038/s41590-023-01504-2
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Is Part of Nature immunology.. Berlin : Springer Nature Limited. 2023, vol. 24, iss. 6, p. 1020-1035.. ISSN 1529-2908. eISSN 1529-2916
Keywords [eng] T cells ; tumor microenvironment ; cancer therapy
Abstract [eng] 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.
Published Berlin : Springer Nature Limited
Type Journal article
Language English
Publication date 2023
CC license CC license description