LAUSR

Circular RNAs (CircRNA) arise from events of non-conventional splicing in which the 3'-tail of an exon back-splices and joins the 5'-head of the upstream exon. Because of their structural conformation, these RNAs are incredibly stable in the cellular space, where they can regulate tumor-associated and anti-immunogenic pathways. Although circRNAs have been profiled in many tumors, their functional contribution to cancer progression is still poorly understood. In the current study, we profiled the most abundant circRNAs expressed in Soft-tissue sarcomas (STS) and characterized them functionally and mechanistically. Surgery and chemotherapy are the standard treatments for STS, but the 5-year survival rate is still below 20% for the advanced cases. Response to immunotherapies, such as immune checkpoint inhibitors, is also marginal for STS, likely because sarcoma cells are not sufficiently immunogenic to recruit a high volume of cytotoxic T cells. To implement discoveries on STS, we recently generated novel immunocompetent STS mouse models and characterized the sarcoma-elicited mechanisms to block immune-recruitment. Interestingly, we observed that two circRNAs, circCsnk1g3, and circAnkib1, promote sarcoma growth by shaping a pro-tumorigenic microenvironment, possibly due to their capabilities to regulate tumor-promoting elements extrinsic to the sarcoma cells. More specifically, we observed that circCsnk1g3 and circAnkib1 control the expression of interferon-related genes and pro-inflammatory factors in the sarcoma cells, thus directing immune cell recruitment into the tumor mass and hence their activation. Mechanistically, we observed that circRNAs might repress pro-inflammatory elements by buffering activation of the pathways mediated by RIG-I, the cytosolic viral RNA sensor. The current findings suggest that targeting specific circRNAs could augment the efficacy of sarcoma immune response to mainstay therapies. Citation Format: Jlenia Guarnerio. Circular RNAs repress interferon responses in the sarcoma cells and promote sarcoma growth by forging a pro-tumorigenic immune microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3652.