Poster Presentation The Melbourne Immunotherapy Network Winter Symposium 2019

γδ- Intraepithelial lymphocytes(γδ- IELs) of the colon: are they potential targets for immunotherapy in colorectal cancer? (#102)

Dinesh Raghu 1 2 , Bhupinder Pal 2 , Yang Liao 3 , Wei Shi 3 , Stephen Wilcox 3 , Kelly Tran 2 , Shoukat Sterle 2 , Ashwini Chand 2 , Matthias Ernst 1 2 , Grant Drummond 4 , Lisa Mielke 2 5
  1. School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
  2. Olivia Newton-John Cancer Research Institute, Heidelberg, VICTORIA, Australia
  3. Walter and Eliza Hall Institute for Medical Research, Melbourne , Australia
  4. Department of Physiology, Anatomy & Microbiology, School of Life Sciences, La Trobe University, Melbourne, Victoria, Australia
  5. School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia

Introduction:Colorectal cancer (CRC) is the 2ndleading cause of cancer death in Australia (Cancer Council, Australia). While surgery, chemotherapy and radiation are first-line treatments, disease recurrence is commonly observed. Recent clinical trials testing the efficiency of immunotherapy (anti-PD1 and anti-CTLA4) in CRC patients, unfortunately show that this treatment is effective only in <10% of patients. These findings highlight the desperate need to identify new targets to develop more efficient CRC-specific immunotherapies.

γδ-IELs are T lymphocytes, found in the epithelial layer of the gastrointestinal (GI) tract, have the ability to sense cellular stress and have an inherent cytotoxic function, but their potential as an anti-cancer agent remains unexplored. A three-way interaction between γδ-IELs, epithelium and microbiota are indispensable for host protection and maintenance of barrier function in the GI tract.

Hypothesis:Colon γδ-IELs are unique and are controlled by the microbiome in maintaining gut barrier function and preventing CRC.

Methodologies:We use mouse models, single-cell RNA sequencing, bulk RNA sequencing, flow cytometry analysis to understand the function of colon γδ-IELs and their role in CRC. 

Results: We show that γδ-IELs are present at variable frequencies in different regions of the GI tract and that colon γδ-IELs express distinct molecular markers of T cell differentiation and function compared with γδ-IELs of the small intestine (SI). In the mice lacking microbiome, factors controlling T cell functions  as TCF-1, Eomes, T-bet are specifically altered in γδ-IELs of the colon but not in SI.  Finally, mice lacking γδ-T cells are more susceptible to carcinogen-and inflammation-induced CRC.

Conclusion:Our findings open a new avenue of exploring and validating colon-specific γδ-IELs as an actionable target in CRC. Our study reveals that γδ-IELs are exquisitely altered by the microbiome in the colon, which will be further investigated in the context of gut immunity, inflammatory disease and CRC.