DNA methylation loss coupled with mitotic cell division promotes immune evasion of tumours with high mutation load

Mitotic cell division increases tumour mutation burden, which stimulates antitumour immune response and contributes to the clinical benefit of immunotherapy. Here we find that markers of cell division also correlate with genomic demethylation involving methylation loss primarily in late-replicating regions termed partial methylation domains (PMDs). Immune-response genes, particularly those involved in cytokine-receptor interaction and interferon signaling, were concentrated in the late-replicating PMDs and transcriptionally repressed in demethylated tumours. Genomic demethylation correlated with immune evasion signatures independently of mutation burden and aneuploidy. Methylome and exome data of our patient cohort for checkpoint blockade in lung cancer demonstrated that genomic demethylation is a predictor of therapeutic resistance of tumours loaded with mutations. The combination of DNA methylation level and mutation burden considerably increased the predictive power. Our results suggest that mitotic cell division results in the contrasting effects of genetic versus epigenetic alterations on tumour immunity and response to immunotherapy.