Simon Eschweiler

Immunotherapies have become crucial treatment options for a variety of cancer types. However, fewer than 30% of people respond to a given therapy. Agonistic immunotherapies were initially considered to mainly activate the CD8+ T cell compartment, without appreciating potential effects on regulatory T cell (TREG) subsets. However, subsequent studies have demonstrated that various immunotherapy drugs suffer from 'on-target/off-cell effects' and 'on-target/off-tumor effects', effectively dampening their treatment efficacy and clinical use. This initially underappreciated mechanism infers that T cell subsets other than CD8+ T cells (i.e. suppressive TREG cells) can express high levels of a given immunotherapy drug target in tumor tissues (on-target/off-cell effects). By binding and activating such suppressive cells, immunotherapies can create an immunosuppressive milieu and thus impede clinical potential and utility. Contrary to that, an overactivation of the immune system in normal tissues (on-target/off-tumor effects), frequently observed by non-specifically targeting TREG cells with anti-CTLA-4 and further exacerbated by combination with anti-PD-1 therapy, can cause severe immune related adverse events (rAEs). Hence, as off-cell effects and widespread immune-related toxicity severely limit both treatment efficacy and combination therapy options, there is urgent need to develop novel immunotherapy targets with an improved efficacy and safety profile. My research is centered around developing such novel therapeutics, focuses on 3 main aspects, and utilizes novel mouse models relevant to tumors and irAEs, next generation sequencing (scRNA-seq, scATAC-seq, ChIP-seq), flow cytometry and imaging techniques. (i)Assess how specific TREG cell subsets develop in tumor tissues and normal, non-malignant organs (ii)Devise and test novel immunotherapeutic strategies through mechanism-guided approaches (iii)Validate novel biomarkers determining agonistic antibody treatment efficacy