Abstract
BackgroundCancer mutations generate novel (neo-)peptides recognised by T cells, but the determinants of recognition are not well characterised. The difference in predicted class I major histocompatibility complex (MHC-I) binding affinity between wild-type and corresponding mutant peptides (differential agretopicity index; DAI) may reflect clinically relevant cancer peptide immunogenicity. Our aim was to explore the relationship between DAI, measures of immune infiltration and patient outcomes in advanced cancer.Patients and methodsCohorts of patients with advanced non-small-cell lung cancer (NSCLC; LUAD, n = 66) and melanoma (SKCM, n = 72) were obtained from The Cancer Genome Atlas. Three additional cohorts of immunotherapy treated patients with advanced melanoma (total n = 131) and NSCLC (n = 31) were analysed. Neopeptides and their clonal status were defined using genomic data. MHC-I binding affinity was predicted for each neopeptide and DAI values summarised as the sample mean DAI. Correlations between mean DAI and markers of immune activity were evaluated using measures of lymphocyte infiltration and immune gene expression.ResultsIn univariate and multivariate analyses, mean DAI significantly correlated with overall survival in 3/5 cohorts, with evidence of superiority over nonsynonymous mutational and neoantigen burden. In these cohorts, the effect was seen for mean DAI of clonal but not subclonal peptides. In SKCM, the association between mean DAI and survival bordered significance (P = 0.068), reaching significance in an immunotherapy-treated melanoma cohort (P = 0.003). Mean DAI but not mutational nor neoantigen burden was positively correlated with independently derived markers of immune infiltration in both SKCM (P = 0.027) and LUAD (P = 0.024).ConclusionsThe association between mean DAI, survival and measures of immune activity support the hypothesis that DAI is a determinant of cancer peptide immunogenicity. Investigation of DAI as a marker of immunologically relevant peptides in further datasets and future clinical studies of neoantigen based immunotherapies is warranted.
Highlights
Cancer mutations encode novelpeptides that can be presented to T cells by major histocompatibility complex (MHC) molecules
Using sequencing data from the Cancer Genome Atlas (TCGA) and three published cohorts of patients with advanced melanoma and lung cancer re-analysed with our peptide affinity prediction pipeline, we investigated the relationship between patient survival, markers of immune activity and DAI, to define whether this measurement is relevant to the human anti-tumour immune response
Amongst all 9mer peptides from the lung adenocarcinoma (LUAD) cohort (n 1⁄4 166 746), we found a strong correlation between probability of anchor residue mutation and DAI predicted for HLA-A, with close to 100% of the most positive and negative DAI peptides mutated at anchor residues P2 and P9
Summary
Cancer mutations encode novel (neo-)peptides that can be presented to T cells by major histocompatibility complex (MHC) molecules. Three additional cohorts of immunotherapy treated patients with advanced melanoma (total n 1⁄4 131) and NSCLC (n 1⁄4 31) were analysed Neopeptides and their clonal status were defined using genomic data. Results: In univariate and multivariate analyses, mean DAI significantly correlated with overall survival in 3/5 cohorts, with evidence of superiority over nonsynonymous mutational and neoantigen burden. In these cohorts, the effect was seen for mean DAI of clonal but not subclonal peptides. Mean DAI but not mutational nor neoantigen burden was positively correlated with independently derived markers of immune infiltration in both SKCM (P 1⁄4 0.027) and LUAD (P 1⁄4 0.024).
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