Exploring the role of Indian Hedgehog in regulating immunogenicity in colorectal cancer

Colorectal cancer (CRC) remains the second-leading cause of cancer-related mortality worldwide, with patients showing varied responses to immunotherapy. Notably, immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in metastatic CRC patients with microsatellite instability (MSI), inducing durable responses in a significant proportion of these patients. In contrast, microsatellite stable (MSS) tumours, which comprise 80-85% of CRC cases, have exhibited limited responses to ICIs. Beyond microsatellite stability status, there is a lack of reliable biomarkers for predicting responses to ICIs, and factors influencing tumour immunogenicity in CRC remains underexplored. Leveraging multi-omic data from The Cancer Genome Atlas, our laboratory has identified Indian Hedgehog (IHH) expression as a potential negative regulator of tumour immunogenicity in CRC. IHH, a member of the Hedgehog family of proteins in vertebrates, is a key signalling molecule that regulates embryonic morphogenesis and adult tissue homeostasis. Despite its known role as a regulator of normal intestinal immunity, its influence on the immune microenvironment in CRC remains largely unexplored. The present thesis provides preliminary insights into the role of IHH in regulating CRC immunogenicity, revealing that IHH, secreted by CRC cells, exerts its immunomodulatory effects primarily through paracrine interactions with the surrounding tumour microenvironment. Specifically, IHH appears to facilitate immune evasion in CRC by downregulating chemokines critical for the recruitment of cytotoxic T lymphocytes (CCL4, CCL5, CXCL10, and CXCL11) in cancer-associated fibroblasts, while skewing the polarization of tumour-associated macrophages toward a more immunosuppressive, less pro-inflammatory phenotype. These findings highlight IHH as a potential modulator of tumour immune responses in CRC and offer potential avenues for targeting IHH signalling to enhance immunotherapy efficacy.