Anti-CMV IgG titer determines organ-specific protection toward immune checkpoint blockade-induced toxicities

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Background Immune-related adverse events (irAEs) post-immune checkpoint blockade (ICB) are a leading cause of patient morbidity. Robust peripheral biomarkers of irAEs are required to improve patient stratification to existing treatment regimens, and these are currently lacking. Seropositivity for human cytomegalovirus (CMV) is associated with protection against severe (grade 3+) irAEs post-ICB; however, the impact of infection on systemic immunity is highly variable. Here, in a prospectively recruited pan-cancer ICB-treated cohort (n=472 patients), we investigate a novel relationship between the relative baseline titer of anti-CMV IgG antibody and organ-specific protection against irAEs. Methods Peripheral blood samples were collected from 472 patients prior to and following one cycle of ICB. CMV serotyping was performed on plasma, while flow cytometry and single-cell RNA/V(D)J sequencing were performed on peripheral blood mononuclear cells. Bulk RNA-sequencing was performed on sorted CD8 + T cells. Serological and phenotyping data were integrated with long-term clinical follow-up of response and irAEs. Results In CMV seropositive patients, whereas anti-CMV IgG antibody level demonstrates stability over years, high pretreatment titer is independently associated with reduced all-organ grade 3+ irAEs. This pan-organ association subdivides into organ-specific effects; protection against non-colitis irAEs being observed only in those with an above median titer of anti-CMV IgG antibody (P High titer vs CMV −=2.1×10 −4 ), whereas CMV-related protection against colitis is unrelated to titer (P Low titer =0.0012, P High titer =0.0031). We demonstrate that anti-CMV IgG antibody titer is robustly coupled to peripheral immune subset composition, with higher anti-CMV IgG titer associated with elevated CD4 + and CD8 + T cell cytotoxicity and effector cell expansion. Conversely, CMV seropositivity is associated with generally reduced circulating T regs cells irrespective of titer. Furthermore, we find exacerbated T cell receptor repertoire skewing toward the largest clones in High Titer individuals, with reduced survival of these clones following ICB treatment. Conclusions This work reinforces the importance of CMV in modulating ICB-induced irAEs, revealing a complex relationship between the degree of humoral anti-CMV immunity and organ-specific protection, while further highlighting the clinical utility of CMV serology in predicting ICB-induced irAEs.