| Autor: |
Arbor G. Dykema, Jiajia Zhang, Boyang Zhang, Laurene S. Cheung, Zhen Zeng, Christopher M. Cherry, Taibo Li, Justina X. Caushi, Marni Nishimoto, Sydney Connor, Zhicheng Ji, Andrew J. Munoz, Wenpin Hou, Wentao Zhan, Dipika Singh, Rufiaat Rashid, Marisa Mitchell-Flack, Sadhana Bom, Ada Tam, Nick Ionta, Yi Wang, Camille A. Sawosik, Lauren E. Tirado, Luke M. Tomasovic, Derek VanDyke, Jamie B. Spangler, Valsamo Anagnostou, Stephen Yang, Jonathan Spicer, Roni Rayes, Janis Taube, Julie R. Brahmer, Patrick M. Forde, Srinivasan Yegnasubramanian, Hongkai Ji, Drew M. Pardoll, Kellie N. Smith |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.12.13.520329 |
| Popis: |
Regulatory T cells (Treg) are conventionally viewed to suppress endogenous and therapyinduced anti-tumor immunity; however, their role in modulating responses to immune checkpoint blockade (ICB) is unclear. In this study, we integrated single-cell RNAseq/TCRseq of >73,000 tumor-infiltrating Treg(TIL-Treg) from anti-PD-1-treated and treatment naive non-small cell lung cancers (NSCLC) with single cell analysis of tumor-associated antigen (TAA)-specific Tregderived from a murine tumor model. We identified 10 subsets of human TIL-Treg, most of which have high concordance with murine TIL-Tregsubsets. Notably, one subset selectively expresses high levels of OX40 and GITR, whose engangement by cognate ligand mediated proliferative programs and NF-kB activation, as well as multiple genes involved in Tregsuppression, in particular LAG3. Functionally, the OX40hiGITRhisubset in the most highly suppressiveex vivoand Tregexpression of OX40, GITR and LAG3, correlated with resistance to PD-1 blockade. Surprisingly, in the murine tumor model, we found that virtually all TIL-Tregexpressing T cell receptors that are specific for TAA fully develop a distinct Th1-like signature over a two-week period after entry into the tumor, down-regulating FoxP3 and up-regulating expression ofTBX21 (Tbet), IFNγ and certain pro-inflammatory granzymes. Application of a gene score from the murine TAA-specific Th1-like Tregsubset to the human single-cell dataset revealed a highly analogous subcluster that was enriched in anti-PD-1 responding tumors. These findings demonstrate that TIL-Tregpartition into multiple distinct transcriptionally-defined subsets with potentially opposing effects on ICB-induced anti-tumor immunity and suggest that TAA-specific TIL-Tregmay positively contribute to anti-tumor responses.One-Sentence SummaryWe define 10 subsets of lung cancer-infiltrating regulatory T cells, one of which is highly suppressive and enriched in anti-PD-1 non-responders and the other is Th1-like and is enriched in PD-1 responders. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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