Chee J, Principe N, Jhala G, Young A.
Funding: WA DOH Future Health and Research Innovation Fund
Lay synopsis: T cells can fail to control cancer or, in autoimmune diseases like type 1 diabetes, stay overactive and damage healthy organs—so we want to understand what drives these opposite outcomes. Using a new mouse model where tumours and pancreatic islets share the same target antigens, we will test how checkpoint immunotherapy and chemotherapy shape T cell behaviour, with the aim of designing stronger, longer-lasting cancer immunotherapies with fewer autoimmune side effects.
Scientific synopsis: T cells drive disease in both cancer and organ-specific autoimmune conditions such as type 1 diabetes, but in opposite ways. In cancer, T cells often fail to maintain sustained cytotoxic activity, allowing tumours to persist and progress. In autoimmunity, cytotoxic T cells remain active and continue to attack healthy tissues, causing ongoing damage. A key population implicated in both settings is progenitor exhausted T cells, a stem-like pool that can replenish effector T cells. Importantly, while these cells can support anti-tumour immunity, their fate and function appear to diverge dramatically between cancer and autoimmune disease models, and the mechanisms underlying this divergence remain poorly understood.
To address this, we have developed novel mouse models in which tumour cells express the same antigens found in pancreatic islet beta cells. Under immune checkpoint blockade, these mice can develop both anti-tumour immunity and autoimmune pathology, allowing us to directly compare antigen-specific T cell fates in tumours versus organs under matched antigen conditions. Critically, we will incorporate chemotherapy as a second, clinically relevant perturbation that can reshape antigen availability and the inflammatory environment, potentially tipping progenitor exhausted T cells toward sustained effector function, or dysfunction.
Using this system, we will dissect the molecular and functional differences between tumour-infiltrating and organ-infiltrating T cells, with a particular focus on progenitor exhausted T cells. By learning what sustains long-term, tissue-damaging T cell activity in autoimmunity, we aim to identify pathways that can be redirected to improve the durability and effectiveness of T cell responses in cancer. This will inform new strategies to enhance immunotherapy while better understanding and managing immune-related toxicity.