Improved neoantigen vaccine selection by combining prediction of pMHC presentation and T-cell epitopes

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We curated two datasets: (1) viral T cell epitopes from IEDB[1] and (2) mutated sequences and T cell responses from four neoantigen vaccine trials[2-5]. We used the viral dataset to several hypotheses related to features which are thought to predict T cell response: hydrophobicity of peptides and their T cell contact residues[6], as well as the relationship between peptide-MHC affinity predictions and a recently developed predictor of eluted ligands. We then examined the same features in the smaller dataset of post-vaccination T cell responses to neoantigens. We found that MHC binding affinity is superior to "eluted ligand" scores as a univariate predictor of T cell response. Additionally, hydrophobicity appears to be moderately predictive of T cell response to viral epitopes but only works as a predictor of response to vaccination in the 2/4 trials which vaccinate with synthetic long peptides, but not mRNA or DC vaccination. Citations: [1] Vita R, Overton JA, Greenbaum JA, Ponomarenko J, Clark JD, Cantrell JR, Wheeler DK, Gabbard JL, Hix D, Sette A, Peters B. The immune epitope database (IEDB) 3.0. Nucleic Acids Res. 2014 Oct 9. pii: gku938. PubMed PMID: 25300482. [2] Carreno, Beatriz M., et al. "A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells." Science 348.6236 (2015): 803-808. [3] Ott, Patrick A., et al. "An immunogenic personal neoantigen vaccine for patients with melanoma." Nature 547.7662 (2017): 217. [4] Sahin, Ugur, et al. "Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer." Nature 547.7662 (2017): 222. [5] Rubinsteyn, Alex, et al. "Computational pipeline for the PGV-001 neoantigen vaccine trial." Frontiers in immunology 8 (2018): 1807. [6] Chowell, Diego, et al. "TCR contact residue hydrophobicity is a hallmark of immunogenic CD8+ T cell epitopes." Proceedings of the National Academy of Sciences (2015): 201500973.

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