Abstract
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.
Highlights
Studies of the tumor microenvironment have surfaced promising avenues of exploration to better understand the clinical relevance of T cell immunobiology
Patient tumor samples analyzed in the current study were restricted to those that were (1) Treg-enriched (q < 0.05) and (2) possessed sufficient clinical drug response labels (Fig. 1).[17]
Our study examined the clinical potential of a 32-gene expression signature to classify patients and their association with chemosensitivity, overall survival (OS), and CD8+ T cell activation/abundance
Summary
Studies of the tumor microenvironment have surfaced promising avenues of exploration to better understand the clinical relevance of T cell immunobiology. We hypothesized that a set of highly variable genes differentially expressed by Tregs (amongst 22 immune cell types)[18] would be able to produce distinct patient clusters from a pool of tumor samples that were all selected due to their enrichment for Tregs.[17] We implemented a pan-cancer approach to identify a favorable immunogenic signature based on immunological expression. We present a 32-gene signature that is able to distinguish a ‘hot’ tumor phenotype associated with chemosensitivity, OS, and CD8+ T cell activation/abundance amongst a pool of 135 Tregenriched patient tumor samples. We conducted a comprehensive expression analysis of a 32-gene
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