Yakou, Marina H., Ghilas, Sonia, Tran, Kelly, Liao, Yang, Afshar-Sterle, Shoukat, Kumari, Anita, Schmid, Kevin, Dijkstra, Christine, Inguanti, Chantelle, Ostrouska, Simone, Wilcox, Jordan, Smith, Maxine, Parathan, Pavitha, Allam, Amr, Xue, Hai Hui, Belz, Gabrielle T., Mariadason, John M., Behren, Andreas, Drummond, Grant R., Ruscher, Roland, Williams, David S., Pal, Bhupinder, Shi, Wei, Ernst, Matthias, Raghu, Dinesh, and Mielke, Lisa A. (2023) TCF-1 limits intraepithelial lymphocyte antitumor immunity in colorectal carcinoma. Science Immunology, 8 (88). eadf2163.

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Abstract

Intraepithelial lymphocytes (IELs), including αβ and γδ T cells (T-IELs), constantly survey and play a critical role in maintaining the gastrointestinal epithelium. We show that cytotoxic molecules important for defense against cancer were highly expressed by T-IELs in the small intestine. In contrast, abundance of colonic T-IELs was dependent on the microbiome and displayed higher expression of TCF-1/TCF7 and a reduced effector and cytotoxic profile, including low expression of granzymes. Targeted deletion of TCF-1 in γδ T-IELs induced a distinct effector profile and reduced colon tumor formation in mice. In addition, TCF-1 expression was significantly reduced in γδ T-IELs present in human colorectal cancers (CRCs) compared with normal healthy colon, which strongly correlated with an enhanced γδ T-IEL effector phenotype and improved patient survival. Our work identifies TCF-1 as a colon-specific T-IEL transcriptional regulator that could inform new immunotherapy strategies to treat CRC.

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