Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer

Zhihao Lü ,Lei Zhang,Ying Hu,Huaibo Sun,Keyan Yang,Jifang Gong,Xiaotian Zhang,Henghui Zhang,Xi Ji ,Jian Li,Zhi Peng,Yujiao Wang,Zhenghang Wang,Jianling Zou,Beibei Mao,Lijia Wu,Shuang Li,Huan Chen,Ming Lu,Lin Shen

doi:10.1186/s13073-021-00997-6

Abstract

BackgroundThe human leukocyte antigen class I (HLA-I) genotype has been linked with differential immune responses to infectious disease and cancer. However, the clinical relevance of germline HLA-mediated immunity in gastrointestinal (GI) cancer remains elusive.MethodsThis study retrospectively analyzed the genomic profiling data from 84 metastatic GI cancer patients treated with immune checkpoint blockade (ICB) recruited from Peking University Cancer Hospital (PUCH). A publicly available dataset from the Memorial Sloan Kettering (MSK) Cancer Center (MSK GI cohort) was employed as the validation cohort. For the PUCH cohort, we performed HLA genotyping by whole exome sequencing (WES) analysis on the peripheral blood samples from all patients. Tumor tissues from 76 patients were subjected to WES analysis and immune oncology-related RNA profiling. We studied the associations of two parameters of germline HLA as heterozygosity and evolutionary divergence (HED, a quantifiable measure of HLA-I evolution) with the clinical outcomes of patients in both cohorts.ResultsOur data showed that neither HLA heterozygosity nor HED at the HLA-A/HLA-C locus correlated with the overall survival (OS) in the PUCH cohort. Interestingly, in both the PUCH and MSK GI cohorts, patients with high HLA-B HED showed a better OS compared with low HLA-B HED subgroup. Of note, a combinatorial biomarker of HLA-B HED and tumor mutational burden (TMB) may better stratify potential responders. Furthermore, patients with high HLA-B HED were characterized with a decreased prevalence of multiple driver gene mutations and an immune-inflamed phenotype.ConclusionsOur results unveil how HLA-B evolutionary divergence influences the ICB response in patients with GI cancers, supporting its potential utility as a combinatorial biomarker together with TMB for patient stratification in the future.

Highlights

The human leukocyte antigen class I (HLA-I) genotype has been linked with differential immune responses to infectious disease and cancer
HLA heterozygosity and HLAI evolutionary divergence (HED) at each of the HLA class I allele (HLA-A), HLA-B, and HLA-C genes were assessed in the peripheral blood mononuclear cell (PBMC) samples (n = 84) using the whole exome sequencing (WES) analysis in the Peking University Cancer Hospital (PUCH) GI cancer cohort (Fig. 1a)
When comparing the distribution patterns of HED for each HLA-A, HLA-B and HLA-C heterozygous genotype in the GI cancer cohort, we found that HLA-C

Summary

Introduction

The human leukocyte antigen class I (HLA-I) genotype has been linked with differential immune responses to infectious disease and cancer. The HLA-I genotype and the concomitant sequence divergence between HLA-I alleles have been linked with immunotherapy efficacy in melanoma and non-small-cell lung cancer (NSCLC) [17, 18]. These studies present evidence that an HLA-I genotype with two alleles with higher sequence divergence, known as the HLAI evolutionary divergence (HED), may enable the presentation of more diverse immunopeptidomes and facilitate subsequent T cell recognition and the adaptive immune response

Methods

Results

Discussion

Conclusion