Identification of Transcriptional Regulators of Immune Evasion Across Cancers: An Alternative Immunotherapeutic Strategy for Cholangiocarcinoma

Abstract

Background: Cancer immune evasion is a multifaceted process that synchronizes pro-tumoral immune infiltration, immunosuppressive inflammation, and inhibitory immune checkpoint expression (IC). Current immunotherapies combat this issue by reinstating immunosurveillance of tumors; however, it benefits a limited patient population. Thus, a more effective immunotherapeutic strategy is warranted to cater to specific patient populations. This investigation introduces a novel immunotherapeutic strategy via inhibition of master regulators of immune evasion (MR-IE). Methods: Samples of the TCGA Pan-Cancer Atlas transcriptomic data were subset and stratified based on IC and estimated immune cell infiltration. Transcriptomic analysis was conducted to unravel pathways associated with the immune evasion process. Transcription factor enrichment and survival analyses were conducted to identify and rank candidate MR-IEs per cancer type. Results: Inhibition of the top-ranking MR-IE candidate of cholangiocarcinoma (CCA), MYC, modulated the gene and protein expression of PD-L1. Moreover, pro-tumoral inflammatory markers, IFNA21 and CX3CL1, were downregulated, and anti-tumoral cytokines, IL-18 and IL-16, were upregulated. Lastly, MYC inhibition potentiated fourth-generation anti-folate receptor alpha (FRα) CAR-T cell therapy against CCA cells. Conclusions: Cumulatively, this study highlights the promise of MR-IE inhibition as a novel potent immunotherapeutic strategy for the treatment of CCA and offers a candidate list of MR-IEs per cancer type for further validation.