Assessment of Functional Status of Human Leukocyte Antigen Class I Genes in Cancer Tissues in the Context of Personalized Neoantigen Peptide Vaccine Immunotherapy

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Abstract
PURPOSE: Accurate human leukocyte antigen (HLA) typing is an essential step for designing peptide vaccines used in the personalized neoantigen peptide vaccine immunotherapy (PNPVT) in patients with cancer. The reasons for variation in the patient response to PNPVT are yet unknown. One of the reasons could be the somatic changes in the HLA genes in the cancer cells. The objective of the present research was to analyze the somatic status of HLA class I genes in cancer tissue through integrative genomic analysis and to identify high-confidence subset of potentially functional cancer somatic HLA class I genotype relevant to PNPVT. PATIENTS AND METHODS: Whole-exome (paired tumor-normal) and RNAseq (tumor) paired-end sequencing data from 24 patients with cancer were used for the analysis. The genotyping of HLA class I was performed using four HLA typing software tools. To assess the functional status of HLA class I genes in the cancer tissue, we analyzed somatic mutation, HLA gene loss of heterozygosity, and chromosome 6 copy loss status in cancer exome data. RESULTS: Somatic mutations in HLA genes were detected in the tumor data of five patients, and somatic HLA gene loss of heterozygosity was identified in the tumor data of five patients. Complete or partial chromosome 6 copy loss was detected in eight patient samples. CONCLUSION: The results indicate that HLA class I genes may get affected by somatic changes in cancer tissue, and assessment of the somatic status of the HLA genotype should be performed in the cancer tissues. The results provide robust rational for removal of mutated or lost HLAs from the personalized neoantigen peptide prediction pipeline to potentially increase the efficacy of the PNPVT. Further functional studies are needed to assess the impact of HLA gene mutations/loss on PNPVT outcomes.

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