TCF-1 limits intraepithelial lymphocyte antitumor immunity in colorectal carcinoma

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 RuscherDavid S. Williams, Bhupinder Pal, Wei Shi, Matthias Ernst, Dinesh Raghu, Lisa A. Mielke

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5 Citations (Scopus)

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.

Original languageEnglish
Article numberadf2163
Number of pages17
JournalScience Immunology
Volume8
Issue number88
DOIs
Publication statusPublished - Oct 2023
Externally publishedYes

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