Pervasiveness of HLA allele-specific expression loss across tumor types

Abstract

Background Efficient presentation of mutant peptide fragments by the human leukocyte antigen class I (HLA-I) genes is necessary for immune-mediated killing of cancer cells. According to recent reports, patient HLA-I genotypes can 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 also 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. Methods Here, we use RNA and whole-exome sequencing data to quantify HLA-I allele-specific expression (ASE) in cancer using our novel method arcasHLA-quant. Results We show that HLA-I ASE loss in at least one of the three HLA-I genes is a pervasive phenomenon across TCGA tumor types. In pancreatic adenocarcinoma, tumor-specific HLA-I ASE loss is associated with decreased overall survival specifically in the basal-like subtype, a finding that we validated in an independent cohort through laser-capture microdissection. Additionally, we show that HLA-I ASE loss is associated with poor immunotherapy outcomes in metastatic melanoma through retrospective analyses. Conclusions Together, our results highlight the prevalence of HLA-I ASE loss and provide initial evidence of its clinical significance in cancer prognosis and immunotherapy treatment.

Loss of Human Leukocyte Antigen and Immune Escape in Head and Neck Cancer

“…The decreased prevalence of HLA LOH with older patient age suggests that the necessity for this immune evasion mechanism may decrease with attenuated antitumor immunity with aging ("immunosenescence"). 41 In the clinical cohort of 120 patients treated with anti-PD-1 immunotherapy, HLA LOH was noted to be enriched in tumors with immunogenic features (higher mutational load and HPV-positivity), suggesting HLA LOH may be selected for as an escape mechanism in these tumors, as has been observed in other cancer types, where immunogenic features such as viral positivity 12 and microsatellite instability 42 have also been associated with HLA LOH. This phenomenon of immune escape may potentially allow HLA LOH to abrogate the favorable effects of these features on immunotherapy response.…”

Germline mechanisms of immunotherapy toxicities in the era of genome‐wide association studies

“…The HLA is a critical mechanism by which immune cells distinguish between self and nonself cells in the immune response, and HLA alleles have been implicated as large-effect genetic drivers for many autoimmune and inflammatory traits. HLA loss of heterozygosity 26 and silencing 27 in the tumor has also been hypothesized as a mechanism for tumor immune evasion. 28 The seminal study of Chowell et al 29 was the first to investigate host HLA allele associations in a large pan-cancer ICI cohort.…”

Gemcitabine Modulates HLA-I Regulation to Improve Tumor Antigen Presentation by Pancreatic Cancer Cells

“…Findings relating to the association of HLA-I expression and patient outcome vary in pancreatic cancer [ 25 , 26 , 27 , 28 ]. Still, HLA-I molecules must be present within the tumor microenvironment for cytotoxic T cell-mediated responses to occur, and high lymphocyte infiltration is considered a favorable prognostic factor in pancreatic cancer [ 29 , 30 ].…”