Conserved transcriptional connectivity of regulatory T cells in the tumor microenvironment informs new combination cancer therapy strategies Journal Article
| Authors: | Glasner, A.; Rose, S. A.; Sharma, R.; Gudjonson, H.; Chu, T.; Green, J. A.; Rampersaud, S.; Valdez, I. K.; Andretta, E. S.; Dhillon, B. S.; Schizas, M.; Dikiy, S.; Mendoza, A.; Hu, W.; Wang, Z. M.; Chaudhary, O.; Xu, T.; Mazutis, L.; Rizzuto, G.; Quintanal-Villalonga, A.; Manoj, P.; de Stanchina, E.; Rudin, C. M.; Pe’er, D.; Rudensky, A. Y. |
| Article Title: | Conserved transcriptional connectivity of regulatory T cells in the tumor microenvironment informs new combination cancer therapy strategies |
| Abstract: | 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. © 2023, The Author(s). |
| Keywords: | vascular endothelial growth factor a; genetics; neoplasm; neoplasms; mouse; animal; metabolism; animals; mice; regulatory t lymphocyte; t-lymphocytes, regulatory; vasculotropin a; tumor microenvironment; humans; human |
| Journal Title: | Nature Immunology |
| Volume: | 24 |
| Issue: | 6 |
| ISSN: | 1529-2908 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2023-06-01 |
| Start Page: | 1020 |
| End Page: | 1035 |
| Language: | English |
| DOI: | 10.1038/s41590-023-01504-2 |
| PUBMED: | 37127830 |
| PROVIDER: | scopus |
| PMCID: | PMC10232368 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding authors are Dana Pe'er and Alexander Rudensky -- Source: Scopus |
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