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

## TL;DR

A new metric called deltaHED helps predict how well patients respond to PD-1 immunotherapy by measuring changes in immune-related genes across three cancer types.

## Contribution

deltaHED is a novel metric that integrates germline and tumour HLA-I divergence to predict immune evasion and survival in PD-1 therapy.

## Key findings

- High deltaHED correlates with increased tumour mutational burden and neoantigen load across three cancer types.
- High deltaHED predicts worse progression-free and overall survival in PD-1 blockade therapy.
- In esophageal cancer, high deltaHED is linked to immunotherapy outcomes but not chemotherapy.

## Abstract

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.

deltaHED predicts survival and immune evasion in PD‐1 blockade therapy: a multi‐cohort study across three cancer types. deltaHED quantifies germlinesomatic HLA‐I divergence and predicts survival and immune evasion in PD‐1 blockade therapy. Across nasopharyngeal carcinoma, melanoma, and esophageal squamous cell carcinoma, high deltaHED is associated with poor prognosis and increased mutations affecting antigen presentation and T‐cell activation. (A) Germline HLA evolutionary divergence (HED) reflects the inherited diversity of human leukocyte antigen (HLA) alleles (e.g., HLA‐A:01:01, HLA‐A:02:01, HLA‐B:07:02, HLA‐B:08:01, HLA‐C:03:03, HLA‐C:07:01), enabling the presentation of diverse immunogenic antigens (different colour in ball) and potential of broad T‐cell activation. (B) Somatic HED: tumour cells undergo loss of heterozygosity (LOH), leading to the loss of specific HLA alleles (e.g., HLA‐A:01:01 LOH, HLA‐B :08:01 LOH, HLA‐C:07:01 LOH) and reduced antigen presentation, resulting in immune evasion. (C) deltaHED (quantifying HLA diversity loss): deltaHED is calculated as the difference between germline HED and somatic HED, reflecting the extent of tumour‐mediated HLA diversity loss. High deltaHED is associated with higher mutation percentage of antigen presentation pathway and poor survival in patients receiving PD‐1 blockade therapy (validated in nasopharyngeal carcinoma [NPC], melanoma, and esophageal squamous cell carcinoma [ESCC] cohorts). HLA alleles: red (HLA‐A), blue (HLA‐B), green (HLA‐C). T cells: green (activated), grey (inactivated). The abstract graph is created in https://BioRender.com.