Abstract 2698: TCF-1 is a critical regulator of intraepithelial lymphocytes in colorectal carcinoma

Abstract Tissue-resident immune cells reside within the gastrointestinal tract known as intraepithelial lymphocytes (T-IELs), including αβ and γδ T-IELs. This unique population of T cells constantly survey and are critical in maintaining the gastrointestinal epithelium. We show that T-IELs in various regions of the gastrointestinal tract have distinct features. T-IELs in the small intestine exhibit high expression of cytotoxic molecules important for cancer defense while colon T-IELs are distinctively regulated by the transcription factor, TCF-7/TCF-1, which suppresses their effector and cytotoxic properties, including reduced expression of granzymes, and their abundance is dependent on the microbiome. Targeted deletion of TCF-1 in γδ T-IELs using pre-clinical mouse models resulted in a distinct effector profile and reduced colon tumor burden. Furthermore, TCF-1 expression was significantly reduced in γδ T-IELs present in human colorectal cancers compared with normal healthy colon, strongly correlating with an enhanced γδ T-IEL effector phenotype and improved patient survival. Further investigation aims to elucidate diverse mechanisms by which TCF-1 controls tissue-specific anti-tumor immunity and uncover the important factors controlling TCF-1 expression. Our study underscores the necessity to consider tumor and organ microenvironment-specific factors in optimizing immunotherapy, advancing our understanding of T cell function in the colon to pave the way for innovative CRC treatments. Citation Format: Marina H. Yakou, Sonia Ghilas, Kelly Tran, Yang Liao, Shoukat Afshar-Sterle, Anita Kumari, Kevin Schmid, Christine Dijkstra, Chantelle Inguanti, Simone Ostrouska, Jordan Wilcox, Maxine Smith, Pavitha Parathan, Amr Allam, Hai-Hui Xue, Gabrielle T. Belz, John M. Mariadason, Andreas Behren, Grant R. Drummond, Roland Ruscher, David S. Williams, Bhupinder Pal, Wei Shi, Matthias Ernst, Dinesh Raghu, Lisa A. Mielke. TCF-1 is a critical regulator of intraepithelial lymphocytes in colorectal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2698.