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.

Abstract

Intraepithelial T lymphocytes in the colon are distinct, and TCF-1 acts to suppress their antitumor immunity.

Editor’s summary

The colon is the most common site of gastrointestinal (GI) cancer, as well as functionally and immunologically distinct from other regions of the GI tract. Intraepithelial T lymphocytes (T-IELs) contribute to host defense by surveilling the epithelium, with specific subsets of gamma-delta (γδ) T-IELs providing protection against colorectal cancer. Yakou et al . used single cell transcriptomics to profile the composition of murine T-IELs from different regions of the GI tract, finding that colon IELs have a suppressed cytotoxic phenotype and express high levels of the transcription factor T cell factor 1 (TCF-1). TCF-1 was required for maintenance of multiple colon T-IEL subtypes yet also suppressed antitumor effector functions among γδ T-IELs. These findings identify distinct features of colon IELs that may suppress immunity against colorectal tumors. —Claire Olingy