T-IELs Could Hold the Key for CRC Immunotherapy

3D rendering of colon cancer: ©SciePro - stock.adobe.com

A study identified how intraepithelial T lymphocyte (T-IEL) groups vary throughout the digestive tract, which could help identify new immunotherapy treatments for colorectal cancer (CRC), according to a study published in Science Immunology.¹

“We have discovered that an important group of immune cells in the large bowel—gamma delta [γδ] T cells—are crucial to preventing bowel cancer,” Lisa Mielke, PhD, head of mucosal immunity and cancer laboratory at the Olivia Newton-John Cancer Research Institute at the La Trobe University School of Cancer Medicine, said in a press release.¹

Investigators at the Olivia Newton-John Cancer Research Institute found that T-IELs in the small intestine expressed cytotoxic molecules important for cancer defense. Conversely, higher levels of T-IELs in the colon displayed more T-cell factor (TCF)-1/TCF-7 expression and reduced effector and cytotoxic profiles. These levels likely indicate that several factors regulate TCF-1 expression in T-IELs. Targeted TCF-1 deletion in γδ T-IELs led to a distinct effector profile and reduced formation of colon tumors in mice.

Researchers hypothesized that the larger microbiota in the colon could drive TCF-1 expression. Comparatively, the small intestine has a smaller microbial population, but is the site of most food digestion. Therefore, it encounters more dietary antigens.

Investigators also noted that TCF-1 expression was reduced in γδ T-IELs that were observed in cases of human CRC compared with a cancer-free colon. This correlated with a greater γδ T-IELs effector phenotype and improved patient outcomes.²

“Our world-first research breakthrough paves a new roadmap for developing targeted combination immunotherapies to more effectively treat bowel cancer patients,” said Marina Yakou, PhD candidate at the Olivia Newton-John Cancer Research Institute and lead co-author of the study, in a press release.¹

In the study, researchers performed single-cell ribonucleic acid sequencing of murine IELs to discover how the populations of IELs in distinctive areas of the GI tract perform immune functions. Flow cytometry was used to measure IELs and their expressed factors. Researchers analyzed over 13,400 IELs from the stomach, small intestine, cecum, and colon. Researchers also compared 200 up-and-down regulated gene expression profiles in the colon and small intestine.²

Researchers look forward to the possibility of better understanding how the gut microbiome and immune cells interact, which could help inform stronger CRC prevention and screening methods in addition to more robust treatment protocols.¹

REFERENCES

1. World-first research breakthrough sparks new hope for bowel cancer patients. News release. Olivia Newton-John Cancer Research Institute. October 7, 2023. Accessed October 10, 2023. https://tinyurl.com/yv2kh6nc

2. Yakou MH, Ghilas S, Tran K, et al. TCF-1 limits intraepithelial lymphocyte antitumor immunity in colorectal carcinoma. Sci Immunol. 2023;8(88):eadf2163. doi:10.1126/sciimmunol.adf2163