Colonic epithelial cathelicidin (LL-37) expression intensity is associated with progression of colorectal cancer and presence of CD8+ T cell infiltrate

Colorectal cancer (CRC) remains a leading cause of cancer mortality. Here, we define the colonic epithelial expression of cathelicidin (LL-37) in CRC. Cathelicidin exerts pleotropic effects including anti-microbial and immunoregulatory functions. Genetic knock out of cathelicidin led to increased size and number of colorectal tumours in the azoxymethane induced murine model of CRC. We aimed to translate this to human disease. The expression
of LL-37 in a large (n=650) fully characterised cohort of treatment naïve primary human colorectal tumours and 50 matched normal mucosa samples with associated clinical and pathological data (patient age, gender, tumour site, tumour stage (UICC), presence or absence of extra-mural vascular invasion, tumour differentiation, mismatch repair protein status, and survival to 18 years) was assessed by immunohistochemistry. The biological consequences of LL37 expression on the epithelial barrier and immune cell phenotype were assessed using targeted qPCR gene expression of epithelial permeability (CLDN2, CLDN4, OCLN, CDH1, TJP1) and cytokine (IL-1β, IL-18, IL-33, IL-10, IL-22, IL-27) genes in a human colon organoid model, and CD3+ , CD4+ and CD8+ lymphocyte phenotyping by immunohistochemistry, respectively. Our data reveal that loss of cathelicidin is associated with human colorectal cancer progression, with a switch in expression intensity an early feature of CRC. LL-37 expression intensity is associated with CD8+ T cell infiltrate, influenced by tumour characteristics including mismatch repair protein status. There was no effect on epithelial barrier gene expression. These data offer novel insights into the contribution of LL-37 to the pathogenesis of CRC and as a therapeutic molecule.