Identifying targets to mitigate immunotherapy-associated immune-related adverse events

About This Grant

PROJECT SUMMARY/ABSTRACT Immunotherapies, mainly immune checkpoint blockade (ICB; e.g., aPD-1 and aCTLA-4), cause immune-related adverse events (irAEs) in 20-30% of cancer patients, with skin and gastrointestinal toxicities being most common. High-dose corticosteroids are typically the first line of treatment for irAEs but timing, resistance and side effects complicate their use and ICB treatment. Critically, the mechanisms driving irAEs remain unclear, limiting the design of targeted therapies that reduce irAEs while preserving anti-tumor activity. In this proposal, we use skin irAEs as a model system to dissect these mechanisms. Our preliminary data showed that neutrophils play a role in both tumor eradication and skin irAEs in T cell therapy, with VISTA+ neutrophils as the predominant population in irAE-affected skin. VISTA targeting reduced irAEs without affecting anti-tumor immunity. Separately, we found that, in non-tumor models, ICB can unleash inflammatory responses from commensal-specific T cells, promoting neutrophil infiltration and irAEs. Notably, metabolic interventions that lower blood glucose (the main energy source for T cells and neutrophils), including caloric restriction (CR) and a pharmacologic CR-mimic, mitigate these irAEs. However, these strategies require further validation in tumor models following ICB for mitigation of irAEs without losing anti-tumor effects. Additionally, we showed that ICB induces loss of regulatory T cells (Tregs), which may disrupt tolerance to skin commensals and allow commensal-specific T cells to cross-react with tumor antigens and drive irAEs. In this scenario, we hypothesize that immunotherapy induces irAEs by activating commensal-specific T cell and pathogenic neutrophil responses, which can be modulated with targeted or metabolic interventions to prevent toxicities while preserving anti-tumor immunity. To test our hypotheses, we propose the following: In Aim 1, we will define the role of VISTA+ neutrophils in irAEs during T cell therapy using VISTA antibodies and knockout (KO) models, complemented with comprehensive immuno-phenotyping analyses. We will also investigate how VISTA+ neutrophils cause irAEs in ex vivo assays and assess VISTA’s value as a skin irAE biomarker using patient samples. In Aim 2, we will assess the therapeutic potential of blood glucose-lowering nutritional (CR) and pharmacological (tirzepatide) interventions in limiting commensal-specific T cell and neutrophil function to reduce irAEs while maintaining anti-tumor responses. We will also directly assess the role of glycolysis in fueling commensal-specific T cells using T cell- specific glycolysis KO and CRISPR models. In Aim 3, we will investigate whether and how ICB disrupts skin commensal tolerance and induces irAEs following ICB and interrogate commensal/tumor T cell cross-reactivity as one of the underlying causes of irAEs via TCR-seq and skin commensal ablation. Our long-term goal is to develop effective therapies that mitigate irAEs while preserving anti-tumor efficacy for improving precision and safety of immunotherapies. With VISTA antibodies already in trials, simple dietary interventions, and FDA-approved tirzepatide, our findings are poised for rapid translation and clinical use.