The introduction of clinical antibodies against programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) has revolutionized cancer treatment. Immune checkpoint blockade has enormous therapeutic potential and is widely prescribed for treating various cancers. However, immune-related adverse events in checkpoint blockade-treated patients are common and limit its clinical application. Despite efforts to understand the etiology of immune-related adverse events, the underlying cellular reactions remain elusive. Recently, our group identified a subset of patients with metastatic melanoma that are predisposed to hepatitis after combined PD-1 and CTLA-4 blockade. These patients are characterized by pre-treatment expansion of effector memory CD4+ T cells (T-EM cells) in blood. We attributed this expansion to chronic or recurrent subclinical immune responses against cytomegalovirus (CMV) infection. Accordingly, baseline expansion of T-EM cells is a reliable biomarker of hepatitis risk that identifies a subgroup of patients who might benefit from prophylactic CMV treatment with valganciclovir.