TCF-1 limits intraepithelial lymphocyte antitumor immunity in colorectal carcinoma.

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.

• Authors: 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
• Journal: Science immunology (Sci Immunol) Vol. 8 Issue 88 Pg. eadf2163 (10 13 2023) ISSN: 2470-9468 [Electronic] United States
• PMID: 37801516 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Antigen, T-Cell, gamma-delta

Topics

• Mice
• Humans
• Animals
• Intraepithelial Lymphocytes (metabolism)
• Receptors, Antigen, T-Cell, gamma-delta
• Intestine, Small
• Epithelium
• Colorectal Neoplasms