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

Genome Medicine

Henghui Zhang¹  Ying Hu¹  Zhi Peng²  Jian Li²  Shuang Li²  Xi Jiao²  Xiaotian Zhang²  Jianling Zou²  Zhihao Lu²  Lin Shen²  Yujiao Wang²  Zhenghang Wang²  Jifang Gong²  Ming Lu²  Keyan Yang³  Huan Chen³  Huaibo Sun³  Lei Zhang³  Lijia Wu³  Beibei Mao³ 

[1]Biomedical Innovation Center, Beijing Shijitan Hospital, School of Oncology, Capital Medical University, Beijing, People’s Republic of China

[2]Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Fu-Cheng Road 52, Hai-Dian District, 100142, Beijing, People’s Republic of China

[3]Genecast Biotechnology Co., Ltd., 88 Danshan Road, Xidong Chuangrong Building, Suite D-401, Xishan District, 214104, Wuxi City, Jiangsu, People’s Republic of China

关键词: Immune checkpoint blockade;    Gastrointestinal cancer;    HLA genotype;    HLA-I evolutionary divergence;    Tumor mutational burden;   

DOI  :  10.1186/s13073-021-00997-6

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY