TCF-1 limits intraepithelial lymphocyte antitumor immunity in colorectal carcinoma

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;Mielke, Lisa A.

Roland Ruscher

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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Science immunology

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2470-9468

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American Association for the Advancement of Science

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DOI

10.1126/sciimmunol.adf2163