Poster Presentation 35th Lorne Cancer Conference 2023

Understanding the role of intraepithelial lymphocytes in colorectal cancer progression (#248)

Lisa Mielke 1 , Dinesh Raghu 1 , Kelly Tran 1 , Yang Liao 1 , Anita Kumari 1 , Kevin Schmid 1 , Shoukat Sterle 1 , Christine Dijkstra 1 , Marina Yakou 1 , Sonia Ghilas 1 , Jordan Wilcox 1 , Maxine E Smith 2 , Pavitha Parathan 1 , Hai-Hui Xue 3 , Gabrielle T Belz 4 , John Mariadason 1 , Matthias Ernst 1 , Andreas Behren 1 , Grant Drummond 5 , Roland Ruscher 2 , Bhupinder Pal 1 , David Williams 6 7 , Wei Shi 1 , Lisa A Mielke 1
  1. School of Cancer Medicine, Olivia Newton-John Cancer Research Institute and La Trobe University, Heidelberg, Victoria, Australia
  2. 2 Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia., Queensland
  3. Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, NJ, USA., Nutley
  4. University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Woolloongabba, QLD 4102, Australia., Woolloongabba
  5. 6 Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology & Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, Australia., Bundoora
  6. Department of Anatomical Pathology, Austin Health, Heidelberg, VIC, Australia., Heidelberg
  7. Department of Clinical Pathology, University of Melbourne, Parkville, VIC, Australia, Parkville

Intraepithelial lymphocytes (IELs), including gd and ab T cells are critical for maintaining the intestinal barrier by sensing microbes, nutrients, and cellular stress. Colorectal carcinoma (CRC) is a leading cause of cancer death and there is a critical need to develop biomarkers for disease progression and develop more effective immunotherapies. The factors regulating IEL development and function in the colon are largely unknown, however they have recently been shown to limit CRC progression. We discover distinct IEL transcriptional programs, developmental requirements and effector phenotypes across individual compartments of the mouse and human gastrointestinal tract. Colon IELs specifically expressed the transcriptional regulator TCF-1. Deletion of TCF-1 released a unique IEL effector profile and eliminated tumours in the colon. In human colorectal carcinoma, we show that TCF-1 expression decreases in IELs compared to healthy colon, this strongly correlated with an enhanced IEL effector phenotype and improved patient survival. Our work identifies TCF-1 as a colon specific IEL transcriptional regulator and will inform strategies to develop novel immunotherapies to treat CRC.