Abstract
Regulatory Tcells (Tregs) can impair anti-tumor immune responses and are associated with poor prognosis in multiple cancer types. Tregs in human tumors span diverse transcriptional states distinct from those of peripheral Tregs, but their contribution to tumor development remains unknown. Here, we use single-cell RNA sequencing (RNA-seq) to longitudinally profile dynamic shifts in the distribution of Tregs in a genetically engineered mouse model of lung adenocarcinoma. In this model, interferon-responsive Tregs are more prevalent early in tumor development, whereas a specialized effector phenotype characterized by enhanced expression of the interleukin-33 receptor ST2 is predominant in advanced disease. Treg-specific deletion of ST2 alters the evolution of effector Treg diversity, increases infiltration of CD8+ Tcells into tumors, and decreases tumor burden. Our study shows that ST2 plays a critical role in Treg-mediated immunosuppression in cancer,highlighting potential paths for therapeutic intervention.
Highlights
The clinical success of immune checkpoint inhibitors in the treatment of non-small cell lung cancer (NSCLC) highlights how targeting immunosuppression in the tumor microenvironment can be an effective therapeutic strategy (Makkouk and Weiner, 2015; Soria et al, 2015)
ScRNA-Seq Reveals Lung-Specific Transcriptional Programs for Tumor-Associated CD4+ Tconvs and Tregs Consistent with prior reports that lung Tregs expand during KP tumor development (Joshi et al, 2015), the fraction of Ki-67+ Tregs by flow cytometry was elevated in lungs with early tumors (Figure 1A), whereas the fraction of Ki-67+ Tconvs was modestly increased at 5 and 8 weeks but returned to baseline by 12 weeks (Figure S1A)
We profiled by full-length scRNA-seq 1,254 Tconvs and 1,679 Tregs from the lungs and mediastinal lymph nodes of non-tumor-bearing and tumor-bearing KP, Foxp3GFP mice along a time course after tumor induction (Figure 1B)
Summary
The clinical success of immune checkpoint inhibitors in the treatment of non-small cell lung cancer (NSCLC) highlights how targeting immunosuppression in the tumor microenvironment can be an effective therapeutic strategy (Makkouk and Weiner, 2015; Soria et al, 2015). Only some patients respond to immune therapies, suggesting that an improved understanding of other immunosuppressive mechanisms is needed for effective treatment. One major mechanism of immunosuppression is posed by CD4+ regulatory T cells (Tregs), which can impair anti-tumor immune responses (Tanaka and Sakaguchi, 2017). Treg depletion can enhance anti-tumor immunity (Bos et al, 2013; Joshi et al, 2015; Marabelle et al, 2013), and antibodies directed against CTLA-4 act in part by depleting Tregs (Simpson et al, 2013)
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