The nucleic acid sensor RIG-I as an inducer of anti-tumor response

Abstract

Abstract The immune microenvironment plays a critical role in tumor progression. Recently, approaches to target Pattern Recognition Receptors (PRRs) have emerged as a promising strategy to enhance immune recognition of tumors. Among the PRRs, those which recognize DNA and RNA in the cells are unique in their ability to respond to both pathogenic and self-nucleic acids that are generated as a result of aberrant cell division/transcription. We previously showed that targeting the DNA sensor three prime exonuclease 1 (TREX1) enhanced immune responses in mouse tumor models. Here we show that the RNA sensor Retinoic acid Induced Gene 1 (RIG-I) acts as a robust immune activator across cancer types. According cBioportal data, expression of RIG-I seems to be a prognostic factor for progression free survival. To functional evaluate RIG-I response in tumor models, we used a hairpin RNA derived from H1N1 sequence. Interestingly, activation of RIG-I increased expression of TREX1 revealing a potential crosstalk between the two pathways. Both breast and colorectal tumor cell lines produce IFN-I after RIG-I activation. Consistently, RNAseq showed upregulation of IFN-I response genes and proinflammatory cytokines across different cell lines. Activation of RIG-I in the tumor cells decreased tumor burden with a concomitant broad cellular and molecular anti-tumor response. Thus, results showed an increase in NK and DC population, while the transcription profile was upregulation of innate immune response genes. Interestingly, tumor growth and NK results were consistent when tumor was implanted in immunocompromised mouse model. Taken together, our findings illustrate how tumor cell RIG-I is a potent inducer of cellular and molecular immune responses.