HLA allele-specific expression loss in tumors can shorten survival and hinder immunotherapy

Abstract

Efficient presentation of aberrant peptide fragments by the human leukocyte antigen class I (HLA-I) genes is necessary for immune detection and killing of cancer cells. Patient HLA-I genotypes are known to impact the efficacy of cancer immunotherapy, and the somatic loss of HLA-I heterozygosity has been established as a factor in immune evasion. While global deregulated expression of HLA-I has been reported in different tumor types, the role of HLA-I allele-specific expression loss - that is, the preferential RNA expression loss of specific HLA-I alleles - has not been fully characterized in cancer. In the present study, we quantified HLA-I allele-specific expression (ASE) across eleven TCGA tumor types using a novel method from input RNA and whole-exome sequencing data. Allele-specific loss in at least one of the three HLA-I genes (ASE loss) was pervasive and associated to worse overall survival across tumor types, including pancreatic adenocarcinomas, prostate carcinomas and glioblastomas, among others. In particular, our analysis shows that detection of neoantigens with binding affinity to the specific HLA-I genes subject to ASE loss was a top prognostic indicator of overall survival. Additionally, we found that ASE loss hindered immunotherapy in retrospective analyses. Together, these results highlight the prevalence of HLA-I ASE loss - a previously uncharacterized phenomenon in cancer - and provide initial evidence of its clinical significance in cancer prognosis and immunotherapy treatment.

Prediction of Immunotherapy Response in Melanoma through Combined Modeling of Neoantigen Burden and Immune-Related Resistance Mechanisms

“…By accounting for these escape mechanisms, and combining them into a composite neoantigen score, we captured a fuller representation of tumor antigen presentation to the immune system compared to simpler models such as TMB, increasing the predictive strength of this biomarker. This approach will likely yield exciting results when applied to non–small cell lung carcinoma and squamous cell carcinoma of the head and neck patient cohorts, as HLA LOH is a prevalent escape mechanism in these, and other tumor types ( 49 ). Indeed, work by Filip and colleagues ( 49 ) which leverages data from >3,500 tumors found allele-specific expression loss at frequencies above 45% in head and neck, lung adenocarcinoma, pancreatic, and prostate cancers.…”

“…This approach will likely yield exciting results when applied to non–small cell lung carcinoma and squamous cell carcinoma of the head and neck patient cohorts, as HLA LOH is a prevalent escape mechanism in these, and other tumor types ( 49 ). Indeed, work by Filip and colleagues ( 49 ) which leverages data from >3,500 tumors found allele-specific expression loss at frequencies above 45% in head and neck, lung adenocarcinoma, pancreatic, and prostate cancers. This, combined with the well-documented prevalence of somatic mutations in class I HLA genes suggests a broad pervasiveness of damaging APM events captured by NEOPS.…”

HLA allele-specific expression: Methods, disease associations, and relevance in hematopoietic stem cell transplantation

“…ArcasHLA, a python-based pipeline was initially developed for HLA genotyping from RNA-seq reads using kallisto, however, the authors later added the feature for allele-specific expression quantification currently allowing both highly accurate HLA typing and expression analysis ( 66 ). By using this novel pipeline, the authors analyzed the clinical significance of HLA class I LOH in multiple tumor types using public RNA-seq data ( 75 ).…”

Prediction of HLA genotypes from single-cell transcriptome data

“…Regulation of HLA expression also extends to the level of individual alleles ( 6 ). Temporal patterns in allele-specific expression (ASE) of certain HLA-DQB1 alleles can discriminate their relative association with type 1 diabetes ( 7 ) and increased ASE imbalance of MHC class I genes was observed in colorectal ( 8 ) and other cancers ( 9 ). Single-cell sequencing allows for fine resolution of ASE and such studies have demonstrated much of the transcriptome is mono-allelically expressed at a given point in time ( 10 – 12 ).…”