Conditional activation of immune-related signatures and prognostic significance: a pan-cancer analysis

Abstract Background It is becoming clear that tumor immune T cell infiltration and its functional orientation have substantial effect on cancer progression, influencing both response to therapy and prognosis. In this pan-cancer study, the previously described Immunologic Constant of Rejection (ICR) signature is used to define opposing immune phenotypes (i.e., immuneactive and immune-silent) across 31 different histologies. We systematically analyze the interconnections between the genetic programming of neoplasms and their immune orientation across different histologies, and the prognostic impact of such interplay. Moreover, we investigated the predictive value of ICR classification across various public datasets of immune checkpoint inhibition therapy. Methods RNA-seq data of samples from a total of 9,282 patient tumor samples representing 31 cancer types were obtained from The Cancer Genome Atlas (TCGA). We classified each cancer type based on the expression of the ICR gene signature. Oncogenic pathway gene set enrichment and mutational status were analyzed in relation to ICR phenotypes. To explore whether tumorintrinsic attributes associate with the prognostic value of ICR across cancers, we compared mutational load, oncogenic alterations and expression of oncogenic pathways between cancer types using an integrative bioinformatic pipeline. Results Our analyses identified a distinct prognostic connotation of ICR depending on cancer histology. We identified several oncogenic pathways whose enrichment inversely correlated with ICR in multiple tumor types. We found several cancer specific pathways that were differentially enriched between tumors in which ICR had a prognostic impact versus the ones in which ICR did not bear any prognostic connotation such as proliferation and TGF-beta signaling. Importantly, this conditional impact of ICR was also validated in the context of immune checkpoint inhibition treatment. Conclusions We identified tumor-intrinsic attributes that correlate with immune phenotypes and potentially influence their development. In addition, a relationship was observed between the enrichment of oncogenic pathways and the prognostic significance of the ICR and its predictive value for patients treated with anti-CTLA4 immune checkpoint inhibition. Such information can be used to prioritize potential candidates for therapies aimed at converting immune-silent into immuneactive tumors and to refine stratification algorithms