Immune heterogeneity within the tumor microenvironment undoubtedly adds several layers of complexity to our understanding of drug sensitivity and patient prognosis across various cancer types. Within the tumor microenvironment, immunogenicity is a favorable clinical feature in part driven by the antitumor activity of CD8+ T cells. However, tumors often inhibit this antitumor activity by exploiting the suppressive function of regulatory T cells (Tregs), thus suppressing the adaptive immune response. Despite the seemingly intuitive immunosuppressive biology of Tregs, prognostic studies have produced contradictory results regarding the relationship between Treg enrichment and survival. We therefore analyzed RNA-seq data of Treg-enriched tumor samples to derive a pan-cancer gene signature able to help reconcile the inconsistent results of Treg studies, by better understanding the variable clinical association of Tregs across alternative tumor contexts. We show that increased expression of a 32-gene signature in Treg-enriched tumor samples (n = 135) is able to distinguish a cohort of patients associated with chemosensitivity and overall survival. This cohort is also enriched for CD8+ T cell abundance, as well as the antitumor M1 macrophage subtype. With a subsequent validation in a larger TCGA pool of Treg-enriched patients (n = 626), our results reveal a gene signature able to produce unsupervised clusters of Treg-enriched patients, with one cluster of patients uniquely representative of an immunogenic tumor microenvironment. Ultimately, these results support the proposed gene signature as a putative biomarker to identify certain Treg-enriched patients with immunogenic tumors that are more likely to be associated with features of favorable clinical outcome.

肿瘤微环境中的免疫异质性无疑为我们对各种癌症类型的药物敏感性和患者预后的理解增加了几层复杂性。在肿瘤微环境中，免疫原性是良好的临床特征，部分由CD8 + T细胞的抗肿瘤活性驱动。但是，肿瘤通常通过利用调节性T细胞（Tregs）的抑制功能来抑制这种抗肿瘤活性，从而抑制了适应性免疫反应。尽管看似直观的Treg免疫抑制生物学，但预后研究在Treg富集与生存之间的关系上却产生了矛盾的结果。因此，我们分析了富含Treg的肿瘤样品的RNA-seq数据，得出了能够帮助调和Treg研究不一致结果的泛癌基因特征，通过更好地了解替代肿瘤背景下Tregs的可变临床关联。我们显示在富含Treg的肿瘤样品中32基因签名的表达增加了（n  = 135）能够区分一组与化学敏感性和总体生存有关的患者。该队列还丰富了CD8 + T细胞的丰度以及抗肿瘤M1巨噬细胞的亚型。随后在更大的Treg富集患者的TCGA池中进行验证（n  = 626），我们的研究结果揭示了一种基因签名，能够产生无监督的Treg富集的患者群体，其中一类患者独特地代表了免疫原性肿瘤微环境。最终，这些结果支持了拟议的基因标记，作为一种可能的生物标记物，用于鉴定某些具有免疫原性肿瘤的富含Treg的患者，这些患者更可能与良好的临床预后相关。