e-Poster Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2021

Intestinal Epithelial TLR4 are Crucial to Chemotherapy Toxicity Development (#200)

Elise Crame 1 , Hannah Rose Wardill 1 2 , Kate Secombe 1 3 , Janet Coller 4 , Joanne Bowen 1
  1. Discipline of Physiology, School of Biomedicine, The University of Adelaide, Adelaide, SA, Australia
  2. Department of Paediatric Oncology/Haematology, The University of Groningen (University Medical Centre Groningen), Groningen, The Netherlands
  3. Diamantina Institute, The University of Queensland, Brisbane, Australia
  4. Discipline of Pharmacology, School of Biomedicine , The University of Adelaide, Adelaide, SA, Australia

Aims: Irinotecan is associated with severe gastrointestinal mucositis (GIM) and causes intestinal damage via activation of Toll-like receptor 4 (TLR4). While previous research shows that tlr4-/- mice are protected from irinotecan-induced GIM, it is unknown if GIM development is dependent on TLR4 signalling through epithelial or immune pathways. This project examined the role of intestinal epithelial TLR4 expression on GIM development and tumour growth following irinotecan.

Methods: Male and female intestinal epithelial conditional TLR4 knockout (Tlr4ΔIEC) mice and wild-type (WT) littermates, bearing subcutaneous colorectal tumours received a single dose of irinotecan (270 mg/Kg i.p.) or vehicle (n = 6-8 per group). The primary outcomes of GIM were change in body weight and diarrhoea, and the outcome for chemoefficacy was tumour size (cm3). All assessments were taken for 72 hours post treatment.

Results: Irinotecan caused moderate GIM characterised by weight loss and diarrhoea in both Tlr4ΔIECand WT mice. Tlr4ΔIEC mice were protected from diarrhoea compared to WT 24 hours after irinotecan (P < 0.0001). Significant weight loss was observed following irinotecan treatment in Tlr4ΔIEC mice compared to vehicle (P = 0.009), however there was no difference in weight loss between WT treated and Tlr4ΔIEC treated mice. Tumour burden did not differ between groups (P > 0.05).

Conclusion: Intestinal epithelial TLR4 plays a more in-depth role in GIM development than previously suspected, with our data suggesting a more potent role for TLR4 expressed on immune cells.