肺肿瘤浸润调节性 T 细胞具有与检查点阻断应答相关的分化转录谱与功能

Regulatory T cells (T reg ) 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 reg (TIL-T reg ) 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 reg derived from a murine tumor model.

We identified 10 subsets of human TIL-T reg , most of which have high concordance with murine TIL-T reg subsets. Only one subset selectively expresses high levels of TNFRSF4 (OX40) and TNFRSF18 (GITR), whose engangement by cognate ligand mediated proliferative programs and NF- B activation, as well as multiple genes involved in T reg suppression, including LAG3 . Functionally, the OX40 hi GITR hi subset is the most highly suppressive ex vivo, and its higher representation among total TIL-T reg correlated with resistance to PD-1 blockade.

Unexpectedly, in the murine tumor model, we found that virtually all TIL-T reg -expressing T cell receptors that are specific for TAA fully develop a distinct T H 1-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 T H 1-like T reg 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 reg partition into multiple distinct transcriptionally defined subsets with potentially opposing effects on ICB-induced antitumor immunity and suggest that TAA-specific TIL-T reg may positively contribute to antitumor responses.