The immunomodulatory role of WNT in intestinal regeneration and cancer

WNT signaling is responsible for regulating proliferation and differentiation of intestinal stem cells (ISCs). The importance of this pathway is highlighted in injury induced regeneration, where pharmalogical inhibition of WNT prevents ISC-dependent regeneration of the intestine. However, aberrant WNT activation is a hallmark of colorectal cancer (CRC), and found in ~85% of patients.

Recently, a link has been discovered between hyperactivation of WNT and poor infiltration of cytotoxic T lymphocytes (CTL) in both human and mouse CRC. Consistently, WNT-mediated CTLs exclusion has also been found in WNT-high crypts in normal intestine and WNT activating regenerating crypts, suggesting that the WNT- mediated CTL exclusion is possibly a conserved mechanism in normal and regenerating intestinal crypts, as well as in cancer.

Therefore, I aim to investigate the relationship between WNT activation and immunosuppression in intestinal regeneration and explore if there is a conserved or context-dependent mechanism between cancer and regeneration. Using the cutting-edge techniques CITE-seq, imaging mass cytometry (IMC) and high- dimensional flow cytometry,

I will spatiotemporally characterize the regenerating intestines upon targeted whole-intestine irradiation. This will be paired with immunomodulation models and pharmalogical inhibition of WNT upon irradiation induced regeneration to determine whether WNT dependent immunomodulation is required for intestinal regeneration. Finally, I will use endoscopy-guided orthotopic transplantation of WNT-high vs WNT-low tumor organoids to determine whether WNT-dependent immunomodulation is conserved between intestinal regeneration and cancer.

Ultimately, these results will provide novel insights into immune cell dynamics upon regeneration, as well as for the development of tumor-specific therapies in WNT-activated CRCs with minimal toxicity.