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

Ross J. Porter, Graeme I. Murray, Abdo Alnabulsi, Matthew P. Humphries, Jacqueline A. James, Manuel Salto-Tellez, Stephanie G . Craig, Ji Ming Wang, Teizo Yoshimura, Mairi H. McLean (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

9 Downloads (Pure)

Abstract

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 knockout 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 LL-37 expression on the epithelial barrier and immune cell phenotype were assessed using targeted quantitative PCR gene expression of epithelial permeability (CLDN2, CLDN4, OCLN, CDH1, and TJP1) and cytokine (IL-1β, IL-18, IL-33, IL-10, IL-22, and 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 CRC 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.

Original languageEnglish
Pages (from-to)495-506
Number of pages12
JournalJournal of Pathology: Clinical Research
Volume7
Issue number5
Early online date14 May 2021
DOIs
Publication statusPublished - Sep 2021

Keywords

  • colorectal cancer
  • LL-37
  • cathelicidin
  • organoid
  • lymphocytes

Fingerprint

Dive into the research topics of 'Colonic epithelial cathelicidin (LL-37) expression intensity is associated with progression of colorectal cancer and presence of CD8+ T cell infiltrate'. Together they form a unique fingerprint.

Cite this