Anti-CMV IgG Titre Determines Organ-Specific Protection Towards Immune Checkpoint Blockade Induced Toxicities
Milotay, G.; Little, M.; Mackay, S.; Muldoon, D.; Huynh, A.-N.; Farkas, A.; Sun, S.; Niu, G.; Tong, O.; Taylor, C. A.; Middleton, M. R.; Klenerman, P.; Fairfax, B. P.
Show abstract
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-=2x10-5), 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.
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