Numerous biomarkers are being tested to enhance the ability of clinicians to predict responses and prognosis after treatment with immune checkpoint inhibitors (ICIs). Polycomb repressive complex 2 (PRC2) is a histone methyltransferase family that plays a major role in chromatin silencing. Preclinical evidence implicates PRC2 components such as enhancer of zeste homolog 2 (EZH2) in immune resistance. This study aimed to assess the clinical relevance of PRC2 mutations in the clinical outcome of ICI-treated patients.

Next-generation sequencing (NGS) data from tumor samples of patients treated with ICIs (anti-PD-1/PD-L1, anti-CTLA-4 or both) were interrogated for alterations in PRC2-related genes. The Kaplan–Meier method was used to assess the association between altered and unaltered PRC2-related genes with overall survival.

Somatic NGS data from 1662 advanced-stage, ICI-treated patients with various primaries (lung, melanoma, bladder, kidney, head neck, esophagogastric, glioma, colorectal, breast, unknown primary) were examined. Seventy patients (4%) harbored truncating or missense mutations or fusions in EZH2 (2.4%), EZH1 (1.2%), SUZ12 (0.9%) or EED (0.7%) genes. Patients carrying alterations in PRC2 genes had significantly longer median overall survival (44 months) compared with those with unaltered tumors (18 months, log-rank P=0.0174). These findings were validated in two additional cohorts of patients (n=313) with various primaries (melanoma, lung, bladder, head neck, anal, sarcoma) who were treated with ICIs.

Inactivating mutations in the PRC2 chromatin silencing machinery, although rare, may predict favorable outcomes in ICI-treated patients with metastatic cancers. This warrants prospective confirmation, and suggests that epigenetic regulators could serve as surrogate markers to guide ICI treatment decisions.