Immune checkpoint blockade induces de novo CD8 T cell priming and innate inflammation leading to myocarditis 3714

Abstract Description Immune checkpoint inhibition (ICI) has dramatically advanced cancer treatment but is associated with adverse outcomes including ICI-induced myocarditis. Recent work demonstrated that T cells restricted to cardiac antigens are indispensable, yet how these cells provoke fatal cardiac damage remains poorly defined. To interrogate the mechanisms underlying myocarditis, we derived a transgenic mouse line with cardiomyocyte-restricted ovalbumin expression. Transfer of naïve OTI T cells into transgenic recipients did not induce pathology, but the addition of ICI led to myocarditis. Critically, PD-1 blockade alone proved sufficient. Our findings suggest that PD-1 blockade facilitates de novo CD8 T cell priming, independent of conventional microbial stimuli. Current work aims to determine if ICI obviates the need for classical 2nd and 3rd priming signals. Additionally, we characterized diseased hearts following CD8 T cell priming and subsequent cardiac infiltration. T cells constitute half of the infiltrating immune cells, while inflammatory monocytes/macrophages and DCs dominate the non-lymphocyte population. Elevations in innate cytokines IL-1β and IL-6 were also identified. We then targeted T cell-mediated innate inflammation to ameliorate disease. Thus, these studies use a novel mouse model to 1) underscore the role for CD8 T cells, 2) reveal a noncanonical activation pathway of CD8 T cells during PD-1 blockade, and 3) posit a role for innate inflammation as a driver of pathology. Funding Sources Supported by AHA predoctoral fellowship (24PRE1198808); NIH/NIAID AI123176; NIH/NHLBI HL156852 Topic Categories Basic Autoimmunity (BA)