Anti-CMV IgG Titre Determines Organ-Specific Protection Towards Immune Checkpoint Blockade Induced Toxicities

Seropositivity for human cytomegalovirus (CMV) is associated with protection against severe (Grade 3+) immune-related adverse events (irAEs) post Immune Checkpoint Blockade (ICB). Here, in a prospectively recruited pan-cancer ICB-treated cohort (n=448 patients), we identify a novel relationship between the relative baseline titre of anti-CMV IgG antibody and organ-specific protection against irAEs. In CMV seropositive patients, whereas anti-CMV IgG antibody level is stable over years, increased pre-treatment titre is independently associated with reduced all-organ Grade 3+ irAEs. This pan-organ association sub-divides into organ-specific effects; protection against non-colitis irAEs being observed only in those with an above median titre of anti-CMV IgG antibody ( P _{High titre} vs. CMV ⁻ =2×10 ⁻⁵ ), whereas CMV-related protection against colitis is unrelated to titre ( P _{Low titre} =0.0016, P _{High titre} =0.0012). We demonstrate that anti-CMV IgG antibody titre is robustly related to peripheral immune subset composition, with higher anti-CMV IgG titre associated with elevated CD4 ⁺ and CD8 ⁺ T cell cytotoxicity and effector cell expansion. Conversely, CMV seropositivity is associated with general reduced circulating Tregs irrespective of titre. This work reinforces the importance of CMV in modulating ICB-induced irAEs, revealing a complex relationship between degree of humoral anti-CMV immunity and organ-specific protection, whilst further highlighting the clinical utility of CMV serology in predicting ICB induced irAEs.