TCF-1 limits intraepithelial lymphocyte antitumor immunity in colorectal carcinoma
journal contribution
posted on 2025-01-08, 04:56 authored by Marina YakouMarina Yakou, Sonia GhilasSonia Ghilas, Kelly TranKelly Tran, Yang Liao, Shoukat Afshar-Sterle, Anita Narendra KUMARI, Kevin Schmid, Christine Dijkstra, Chantelle Inguanti, Simone OstrouskaSimone Ostrouska, Jordan Wilcox, Maxine Smith, Pavitha ParathanPavitha Parathan, Amr AllamAmr Allam, Hai-Hui Xue, Gabrielle T Belz, John MariadasonJohn Mariadason, Andreas BehrenAndreas Behren, Grant DrummondGrant Drummond, Roland Ruscher, David WilliamsDavid Williams, Bhupinder PalBhupinder Pal, Wei ShiWei Shi, Matthias ErnstMatthias Ernst, Dinesh Raghu, Lisa MielkeLisa MielkeIntraepithelial 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.
