{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Dykema AG"],"funding":["NIBIB NIH HHS","NHGRI NIH HHS","NCI NIH HHS","NIGMS NIH HHS"],"pagination":["eadg1487"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10629528"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["8(87)"],"pubmed_abstract":["Regulatory T cells (T<sub>reg</sub>) are conventionally viewed as suppressors of endogenous and therapy-induced antitumor immunity; however, their role in modulating responses to immune checkpoint blockade (ICB) is unclear. In this study, we integrated single-cell RNA-seq/T cell receptor sequencing (TCRseq) of >73,000 tumor-infiltrating T<sub>reg</sub> (TIL-T<sub>reg</sub>) from anti-PD-1-treated and treatment-naive non-small cell lung cancers (NSCLC) with single-cell analysis of tumor-associated antigen (TAA)-specific T<sub>reg</sub> derived from a murine tumor model. We identified 10 subsets of human TIL-T<sub>reg</sub>, most of which have high concordance with murine TIL-T<sub>reg</sub> subsets. Only one subset selectively expresses high levels of <i>TNFRSF4</i> (OX40) and <i>TNFRSF18</i> (GITR), whose engangement by cognate ligand mediated proliferative programs and NF-κB activation, as well as multiple genes involved in T<sub>reg</sub> suppression, including <i>LAG3</i>. Functionally, the OX40<sup>hi</sup>GITR<sup>hi</sup> subset is the most highly suppressive ex vivo, and its higher representation among total TIL-T<sub>reg</sub> correlated with resistance to PD-1 blockade. Unexpectedly, in the murine tumor model, we found that virtually all TIL-T<sub>reg</sub>-expressing T cell receptors that are specific for TAA fully develop a distinct T<sub>H</sub>1-like signature over a 2-week period after entry into the tumor, down-regulating <i>FoxP3</i> and up-regulating expression of <i>TBX21 (</i>Tbet)<i>, IFNG</i>, and certain proinflammatory granzymes. Transfer learning of a gene score from the murine TAA-specific T<sub>H</sub>1-like T<sub>reg</sub> subset 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-T<sub>reg</sub> partition into multiple distinct transcriptionally defined subsets with potentially opposing effects on ICB-induced antitumor immunity and suggest that TAA-specific TIL-T<sub>reg</sub> may positively contribute to antitumor responses."],"journal":["Science immunology"],"pubmed_title":["Lung tumor-infiltrating T&lt;sub&gt;reg&lt;/sub&gt; have divergent transcriptional profiles and function linked to checkpoint blockade response."],"pmcid":["PMC10629528"],"funding_grant_id":["P30 CA006973","R37 CA251447","R01 EB029455","R01 HG010889","R01 CA121113","R01 HG009518","T32 CA009110","K99 HG011468","T32 GM136577","R01 CA142779"],"pubmed_authors":["Nishimoto M","Zhang J","Bom S","Taube J","Mitchell-Flack M","Smith KN","Zhan W","Aye THK","Cherry CM","Hou W","Yegnasubramanian S","Anagnostou V","Ionta N","VanDyke D","Connor S","Wang Y","Zhang B","Dykema AG","Brahmer JR","Cheung LS","Munoz AJ","Ji H","Spicer J","Zeng Z","Caushi JX","Tam A","Singh D","Forde PM","Tomasovic LM","Zhang T","Li T","Rashid R","Rayes R","Ji Z","Tirado LE","Spangler JB","Sawosik CA","Yang S","Pardoll DM"],"additional_accession":[]},"is_claimable":false,"name":"Lung tumor-infiltrating T&lt;sub&gt;reg&lt;/sub&gt; have divergent transcriptional profiles and function linked to checkpoint blockade response.","description":"Regulatory T cells (T<sub>reg</sub>) are conventionally viewed as suppressors of endogenous and therapy-induced antitumor immunity; however, their role in modulating responses to immune checkpoint blockade (ICB) is unclear. In this study, we integrated single-cell RNA-seq/T cell receptor sequencing (TCRseq) of >73,000 tumor-infiltrating T<sub>reg</sub> (TIL-T<sub>reg</sub>) from anti-PD-1-treated and treatment-naive non-small cell lung cancers (NSCLC) with single-cell analysis of tumor-associated antigen (TAA)-specific T<sub>reg</sub> derived from a murine tumor model. We identified 10 subsets of human TIL-T<sub>reg</sub>, most of which have high concordance with murine TIL-T<sub>reg</sub> subsets. Only one subset selectively expresses high levels of <i>TNFRSF4</i> (OX40) and <i>TNFRSF18</i> (GITR), whose engangement by cognate ligand mediated proliferative programs and NF-κB activation, as well as multiple genes involved in T<sub>reg</sub> suppression, including <i>LAG3</i>. Functionally, the OX40<sup>hi</sup>GITR<sup>hi</sup> subset is the most highly suppressive ex vivo, and its higher representation among total TIL-T<sub>reg</sub> correlated with resistance to PD-1 blockade. Unexpectedly, in the murine tumor model, we found that virtually all TIL-T<sub>reg</sub>-expressing T cell receptors that are specific for TAA fully develop a distinct T<sub>H</sub>1-like signature over a 2-week period after entry into the tumor, down-regulating <i>FoxP3</i> and up-regulating expression of <i>TBX21 (</i>Tbet)<i>, IFNG</i>, and certain proinflammatory granzymes. Transfer learning of a gene score from the murine TAA-specific T<sub>H</sub>1-like T<sub>reg</sub> subset 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-T<sub>reg</sub> partition into multiple distinct transcriptionally defined subsets with potentially opposing effects on ICB-induced antitumor immunity and suggest that TAA-specific TIL-T<sub>reg</sub> may positively contribute to antitumor responses.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Sep","modification":"2026-05-28T22:28:57.347Z","creation":"2025-04-06T08:04:15.126Z"},"accession":"S-EPMC10629528","cross_references":{"pubmed":["37713507"],"doi":["10.1126/sciimmunol.adg1487"]}}