Arshad Ayyaz

Last decade has seen immunotherapy emerging as revolutionary anti-cancer treatment. Indeed, early clinical trials found a subset of patients with difficult-to-treat melanoma and lung cancer achieve long-term stable response. Subsequent studies found that these hypermutated cancers express ample peptide neo-antigens and are therefore readily detected as ‘non-self’ and eliminated by the therapeutically stimulated cytotoxic lymphocytes. However, most cancers contain relatively stable genome and do not respond to this treatment. For example, about 85% of all colorectal cancers (CRCs) show microsatellite stability, leading to poor response to immunotherapy. Consequently, a median 5-years survival in CRC patients with metastatic disease remains 12.5% making it a leading cause of cancer deaths globally. Thus, there is an urgent need to understand how transformed tissues evade immunity and find new ways to treat cancer patients. Tumor cells with stem cell-like properties that have long been associated with poor prognosis are now emerging as major players in resistance against immunotherapy, as shown by multiple pre-clinical studies. These cells, often referred to as tumor-initiating cells (TICs), can escape lymphocyte detection despite antigen editing, immune checkpoint inhibition or targeted T cell therapy, suggesting that tumor-mediated intrinsic processes, rather than lymphocyte dysfunction, drive immune escape in several tumors.

Our work is focused on understanding how regenerative somatic cells survive immune surveillance during genotoxic stress, what suppresses accumulation of somatic mutations under these conditions, how rare oncogenic genomic alterations escape these checkpoints, and what components of these mechanisms are hijacked by the transformed tissues which promotes their own growth and survival. We are using 3D organoids, tumor organoid-immune cell co-cultures, single cell-multiomics, functional genomics and targeted genome editing approaches to address these questions. Results from these studies are expected to provide novel therapeutic targets that could be used to develop better combination immunotherapeutic treatments that will improve clinical outcome in cancer patients.