Abstract PO-095: Intrinsic and acquired resistance to RIG-I induced anti-tumor responses

Abstract

Abstract The immune microenvironment plays a critical role in cancer orchestrating tumor progression and response to therapeutics. Strategies to manipulate the tumor immune microenvironment are invaluable to complement current standard of care treatments. Recently, approaches to target Pattern Recognition Receptors (PRRs) that recognize intracellular and extracellular pathogens have emerged as a promising strategy to enhance immune recognition of tumors. Among the PRRs, intracellular receptors that 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 a cytosolic DNA sensor three prime exonuclease 1 (TREX1) enhanced immune responses in mouse tumor models including colorectal carcinomas (CRCs). Here we show that a cytosolic RNA sensing pathway, Retinoic acid Induced Gene 1 (RIG-I) acts as a robust immune activator across cancer types by enhancing the cellular and molecular correlates of anti-tumor immune responses. Using a stem loop hairpin RNA structure derived from a H1N1 sequence we elicited a potent RIG-1 response in CRC and breast cancers. Interestingly, activation of RIG also increased expression of TREX1 revealing potential cross-talk between the two pathways. We show that activation of tumor cell RIG-I alone is sufficient to decrease tumor burden with a concomitant broad cellular and molecular anti-tumor response. We observed a group of negative regulators of immune responses, including the NKG2a ligand - HLA-E, mono PARPs and the inhibitory checkpoint protein LAG3, are upregulated in RIG high tumors in cell culture, mouse and human tumors indicating how RIG-I high tumors may develop resistance to immune killing. Combination of RIG-I agonists synergized with inhibition of these resistance mechanisms in a tumor and context dependent manner. To understand intrinsic resistance to RIG signaling, we performed a focused RNAi screen and identified critical positive and negative modulators of RIG-I function in tumor cells. Taken together, our findings illustrate how tumor cell RIG-I is a potent inducer of cellular and molecular immune responses. Our work also highlights tumor cell intrinsic and extrinsic pathways that confer resistance to RIG-I induced anti-tumor responses and provide strategies to mitigate such resistance. Citation Format: Sudarshan Anand, Eugenia Fraile-Bethencourt, Sokchea Khou. Intrinsic and acquired resistance to RIG-I induced anti-tumor responses [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-095.