Dataset Information

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

ABSTRACT:

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.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13073-021-00997-6.

SUBMITTER: Lu Z

PROVIDER: S-EPMC8567649 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIt is assumed that loss of heterozygosity and allelic copy loss in HLA gene is associated with poor response rates in immune checkpoint inhibitor treatment. H-owever, the accurate extents or consistency in cancer types have not been explored.ObjectiveThe goal of this study is to investigate quantitative relationship between HLA allelic copy loss and response rates to immune checkpoint inhibitors. Also, tumor microenvironment was computationally assessed in the tumors with HLA copy loss to provide potential mechanisms for the relationships.MethodA total of 282 whole exome sequencing data from three cohorts of patients who received immune checkpoint blockade immunotherapy were analyzed, including Anti-PDL1 treated in metastatic urothelial cancer (N = 216), anti-PD1 treated metastatic melanoma (N = 26), and anti-CTLA4 treated metastatic melanoma (N = 39). The LOHHLA algorithm was used to calculate allelic copy number loss at each HLA-A, -B, and -C locus, and further determine HLA allelic copy loss status. The HLA copy status and ICB response rates were analyzed for association using Fisher's exact test. The CIBERSORT-absolute algorithm was then used to analyze the patient's immune environment, which represented loss of heterozygosity, using paired matched RNA sequencing data.ResultsUnlike the general expectation, HLA allelic copy loss was not significantly associated with the ICB responses. Moreover, the relationship showed a reversed relationship in HLA-A in the urothelial cancer (better ICB response in HLA copy loss). Regardless of the HLA copy status, the proportion of cytotoxic immune cells in the immune environment of patients was correlated with ICB response, which was higher in the loss of heterozygosity group in the urothelial cohort.ConclusionAlthough the loss of heterozygosity in HLA was generally expected to be an inhibitory factor in the immune treatment response by causing T cell immune evasion, our analysis demonstrates no explicit relationships.