Colorectal cancer (CRC) is the 2nd leading cause of cancer death in Australia, with ~15,000 new cases and ~5,300 deaths in Australia annually (Cancer Australia). Despite the success of immunotherapy drugs for many types of cancers, over 95% of CRC patients remain refractory to these treatments. Furthermore, current immunotherapies are associated with autoimmune-like side-effects, creating an urgency to develop CRC-specific immunotherapies to overcome these adverse events and enable more improved responses for CRC patients. Unpublished data from the Mielke Lab shows intraepithelial lymphocytes (IELs), particularly gd T-IELs, are important for controlling CRC development and progression, highlighting their potential as anti-cancer agents. IELs are among the mucosal immune cells which protect the gut barrier. These unique and heterogenous populations of tissue-resident immune cells are interspersed within the gut epithelium, predominantly comprising ab and gd T cells. IELs can sense epithelial cell stress, changes in the gut microbiome, and have inherent cytotoxic abilities. However, factors regulating these functions in the colon are unknown.
Investigating the molecular mechanisms underpinning the anti-tumour properties of IELs could uncover solutions to hurdles posed by CRC and elucidate novel immunotherapy targets for improved treatment options.Using scRNA sequencing, we have identified IELs with high expression of cytokine receptors: IL-21R and IL-2Rb in the colon of naïve mice. The role of IL-21 on IEL development and function is unknown, while cytokines such as IL-15 and IL-2 are well recognized as being critical for T-IEL development but, their role in IEL function remains largely unexplored. Our preliminary data has uncovered that IL-21 promotes IEL cytotoxic effector functions in the colon of naïve mice. Further investigation is ongoing to understand how these cytokines influence IELs at steady state and in cancer. This will allow us to better tailor CRC- specific immunotherapies that harness the full anti-tumour capabilities of IELs.