.png){kind=icon}
.png){kind=icon}
Return
Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer
.png){kind=icon}
OA
AI
L
J
W
L
H
L
G
L
J
K
H
M
Z
Z
P
陆
W
Z
S
DOI：10.1186/s13073-021-00997-6.png)
.png){kind=icon}
.png){kind=icon}
Share.png){kind=icon}
Save
Abstract
En 中文
Background The 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. Methods This 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. Results Our 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. Conclusions Our 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.
Keywords:
Immune checkpoint blockade
Gastrointestinal cancer
HLA genotype
HLA-I evolutionary divergence
Tumor mutational burden
AI Summary
Key information extracted from the uploaded paper, including a brief overview, abstract, background, key highlights, visual analysis, and future outlook.
Journal
IF:
11.2
Papers:
2.3K
Citations:
1.4W
Organization
Cited Papers