Abstract 1352: SOX17 plays a critical role in immune evasion of colorectal cancer

Abstract Colorectal cancers (CRCs) are a leading cause of cancer-related death. Most CRCs are immune cold, and do not respond to checkpoint blockade therapy except for microsatellite-high CRCs harboring high mutational burdens. Deciphering the mechanism by which CRC cells evade immune surveillance has the potential to dramatically improve the prognosis of CRC patients. During tumor evolution of CRCs, epigenetic changes play critical roles in addition to accumulation of genetic mutations. However, distinct mutational patterns and patient backgrounds render it challenging to distinguish the driver epigenetic alterations from passenger epigenetic alterations induced by gene mutations or other environmental factors. Identification of the driver epigenetic alterations may provide novel mechanistic insights into colon cancer biology including how they evade immune surveillance. Here, we utilized the colon cancer organoid orthotopic transplantation approach to establish colon cancer organoids from different stages of the tumors, and performed comprehensive epigenomic and transcriptomic analyses to understand the epigenetic alterations during tumor evolution. We found that in vivo environment induces epigenetic alterations that converge on SOX17, a transcription factor that is required for endoderm development. SOX17 is re-expressed in colon cancers in vivo, but not in the in vitro organoid culture, and reprograms tumor cell fate with fetal intestinal gene expressions. Importantly, SOX17 knockout leads to tumor rejection in immunocompetent mice, but not in immunodeficient mice, by turning immune cold tumors into hot tumors with robust intratumoral infiltration of activated CD8+ T cells. Mechanistically, SOX17 directly downregulates Ifngr1 expression and mitigates MHC-I expression to evade CD8+ T cell-mediated tumor cell killing. Together, our result reveals that SOX17 is a master transcription factor that induces the in vivo epigenetic reprograming of tumors, which contributes to the immune evasion of colon cancers. Citation Format: Norihiro Goto, Saori Goto, Peter Westcott, Shinya Imada, Judith Agudo, Omer Yilmaz. SOX17 plays a critical role in immune evasion of colorectal cancer [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 1352.