Identifying and modulating pathologic T cells that govern oral mucosal immune related adverse events from immune checkpoint blockade

Immune related adverse events (irAEs) secondary to checkpoint blockade inhibition (CBI) or other immune modulatory therapy for cancer, including head and neck cancers, are a significant problem given the increasing use of CBI and other immunomodulatory agents. It is therefore of critical importance to improve understanding and optimize treatment regimens for irAEs. Oral mucosal irAE toxicity is relatively understudied despite the potentially significant morbidity to patients. Understanding oral mucosal irAEs is an immediately accessible window into the autoimmune pathology caused by ICB. Lessons from oral mucosal irAEs thus can inform approaches to other irAEs. Our objective is to define T cell-based mechanisms of oral mucosal irAEs due to anti- PD-1 therapy. This work will also further our goal to identify predictive markers of oral mucosal irAEs through improved knowledge of their pathogenesis. Our central hypotheses are that regulatory T cell (Treg) plasticity is a major driver of oral mucosal irAEs, with IL-17A being a key cytokine driver of mucosal toxicity. These hypotheses build on prior work to define molecular signatures of T cells causative of muco-cutaneous eruptions. We will test these hypotheses using an innovative combination of approaches including analysis of human samples, mouse models that can generate similarly behaving irAEs, and generation and analysis of patient- derived organoids (PDOs). Our team of experts in immunology, immunotherapy, head and neck cancer, and bioinformatics will test this central hypothesis and achieve our objective via the following specific aims: 1) Determine functional significance of Treg and Th17 balance in oral mucosal irAEs. 2) Investigate mechanistically focused strategies to mitigate mucosal irAEs in murine models. 3) Validate therapeutic strategies to mitigate irAEs in patient-derived irAE organoid models. We will utilize our expertise in single cell RNA sequencing and PDOs to accomplish these aims. At the end of the project, the expected outcome is to better understand the pathophysiological mechanisms of oral mucosal irAEs and have identified strategies that can treat or modulate these, for future clinical trials. We will also be able to generate the mechanistic basis for future strategies to rapidly mitigate or even prevent these irAEs, which will ultimately benefit HNSCC and other cancer patients.