deltaHED predicts survival and immune evasion in PD‐1 blockade therapy: A multi‐cohort study across three cancer types

The prognostic relevance of HLA class I (HLA-I)-mediated immunity in cancer immunotherapy remains unclear. We introduce deltaHED, a novel metric that quantifies evolutionary divergence between germline and tumour-acquired HLA-I alleles, integrating both inherited and somatic immunogenetic variation. Using whole-exome sequencing, we analysed deltaHED across three independent cohorts: 164 patients with recurrent/metastatic nasopharyngeal carcinoma (RM/NPC) from the POLARIS-02 trial (PD-1 monotherapy), 88 melanoma patients receiving PD-1 monotherapy, and 477 esophageal squamous cell carcinoma (ESCC) patients from the JUPITER-06 trial (PD-1 plus chemotherapy vs. chemotherapy alone). High deltaHED was significantly associated with increased tumour mutational burden and neoantigen load (p < .001), but predicted worse progression-free survival (PFS) and overall survival (OS) in patients receiving PD-1 blockade across all three cancers. In ESCC, this association was observed only in the immunotherapy arm, not in patients treated with chemotherapy alone. High deltaHED also correlated with increased mutations in antigen-processing and T-cell receptor pathways. These findings establish deltaHED as a clinically relevant biomarker of immune divergence with potential to improve patient stratification and guide personalised immunotherapy strategies.