pr3c00491_si_004.xlsx (138.09 kB)
Proteogenomics Reveal the Overexpression of HLA‑I in Cancer
datasetposted on 2023-10-19, 22:43 authored by Ying Wang, David Fenyö
An accurate quantification of HLA class I gene expression is important in understanding the interplay with the tumor microenvironment of antitumor cytotoxic T cell activities. Because HLA-I sequences are highly variable, standard RNAseq and mass spectrometry-based quantification workflows using common genome and protein sequence references do not provide HLA-I allele specific quantifications. Here, we used personalized HLA-I nucleotide and protein reference sequences based on the subjects’ HLA-I genotypes and surveyed tumor and adjacent normal samples from patients across nine cancer types. Mass spectrometry using data dependent acquisition data was validated to be sufficient to estimate HLA-A protein expression at the allele level. We found that HLA-I proteins were present in significantly higher levels in tumors compared to adjacent normal tissues from 41 to 63% of head and neck squamous cell carcinoma, uterine corpus endometrial carcinoma, and clear cell renal cell carcinoma patients, and this was driven by increased levels of HLA-I gene transcripts. Most immune cell types are universally enriched in HLA-I high tumors, while endothelial and neuronal cells showed divergent relationships with HLA-I. Pathway analysis revealed that tumor senescence and autophagy activity influence the level of HLA-I proteins in glioblastoma. Genes correlated to HLA-I protein expression are mostly the ones directly involved in HLA-I function in immune response and cell death, while glycosylation genes are exclusively co-expressed with HLA-I at the protein level.
pathway analysis revealedones directly involvedautophagy activity influenceadjacent normal tissuesadjacent normal samplessignificantly higher levelsallele specific quantificationsprotein sequence referencesused personalized hlasubjects ’ hlaimmune cell typesincreased levelsimmune responseprotein expressioncell deathcell activitiesallele levelprovide hlahla ‑hla classestimate hlauniversally enrichedtumors comparedtumor senescencetumor microenvironmentsurveyed tumorstandard rnaseqproteogenomics revealprotein levelmass spectrometryhighly variablehigh tumorsglycosylation genesgenes correlatedgene transcriptsgene expressionexclusively coantitumor cytotoxicaccurate quantification