作者
Arbor G. Dykema,Jiajia Zhang,Laurene S. Cheung,Sydney Connor,Boyang Zhang,Zhen Zeng,Christopher Cherry,Taibo Li,Justina X. Caushi,Marni Nishimoto,Andrew J. Munoz,Zhicheng Ji,Wenpin Hou,Ws Zhan,Dipika Singh,Taoping Zhang,Rufiaat Rashid,Marisa Mitchell-Flack,Sadhana Bom,Ada Tam,Nick Ionta,Thet H. K. Aye,Yi Wang,Camille A. Sawosik,Lauren E. Tirado,Luke M. Tomasovic,Derek VanDyke,Jamie B. Spangler,Valsamo Anagnostou,Stephen C. Yang,Jonathan Spicer,Roni F. Rayes,Janis M. Taube,Julie R. Brahmer,Patrick M. Forde,Srinivasan Yegnasubramanian,Hongkai Ji,Drew M. Pardoll,Kellie N. Smith
摘要
Regulatory T cells (Treg) 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 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 Treg derived from a murine tumor model. We identified 10 subsets of human TIL-Treg, most of which have high concordance with murine TIL-Treg subsets. Only one subset selectively expresses high levels of TNFRSF4 (OX40) and TNFRSF18 (GITR), whose engangement by cognate ligand mediated proliferative programs and NF-κB activation, as well as multiple genes involved in Treg suppression, including LAG3. Functionally, the OX40hiGITRhi subset is the most highly suppressive ex vivo, and its higher representation among total TIL-Treg correlated with resistance to PD-1 blockade. Unexpectedly, in the murine tumor model, we found that virtually all TIL-Treg-expressing T cell receptors that are specific for TAA fully develop a distinct TH1-like signature over a 2-week period after entry into the tumor, down-regulating FoxP3 and up-regulating expression of TBX21 (Tbet), IFNG, and certain proinflammatory granzymes. Transfer learning of a gene score from the murine TAA-specific TH1-like Treg 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-Treg partition into multiple distinct transcriptionally defined subsets with potentially opposing effects on ICB-induced antitumor immunity and suggest that TAA-specific TIL-Treg may positively contribute to antitumor responses.