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Deep neural networks predict class I major histocompatibility complex epitope presentation and transfer learn neoepitope immunogenicity

Nature Machine Intelligence volume 5, pages 861–872 (2023)Cite this article

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A preprint version of the article is available at bioRxiv.

Abstract

Identifying neoepitopes that elicit an adaptive immune response is a major bottleneck to developing personalized cancer vaccines. Experimental validation of candidate neoepitopes is extremely resource intensive and the vast majority of candidates are non-immunogenic, creating a needle-in-a-haystack problem. Here we address this challenge, presenting computational methods for predicting class I major histocompatibility complex (MHC-I) epitopes and identifying immunogenic neoepitopes with improved precision. The BigMHC method comprises an ensemble of seven pan-allelic deep neural networks trained on peptide–MHC eluted ligand data from mass spectrometry assays and transfer learned on data from assays of antigen-specific immune response. Compared with four state-of-the-art classifiers, BigMHC significantly improves the prediction of epitope presentation on a test set of 45,409 MHC ligands among 900,592 random negatives (area under the receiver operating characteristic = 0.9733; area under the precision-recall curve = 0.8779). After transfer learning on immunogenicity data, BigMHC yields significantly higher precision than seven state-of-the-art models in identifying immunogenic neoepitopes, making BigMHC effective in clinical settings.

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Fig. 1: Experimental procedure.
Fig. 2: BigMHC network architecture and pseudosequence composition.
Fig. 3: EL prediction results.
Fig. 4: Performance of immunogenicity predictions for all methods.

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Data availability

All data, including model outputs and MANAFEST data, are provided in our public Mendeley repository: https://data.mendeley.com/datasets/dvmz6pkzvb. All data except MANAFEST data were collected from publicly available sources: MHCflurry-2.02, NetMHCpan-4.16, PRIME-1.013, PRIME-2.014, TESLA16, IEDB22, NEPdb23, Neopepsee24, IPD-IMGT/HLA34, IPD-MHC 2.035 and UniProt36 (accession numbers: P01899, P01900, P14427, P14426, Q31145, P01901, P01902, P04223, P14428, P01897, Q31151). Source data are provided with this paper.

Code availability

All code used in this study and the final trained models are provided in our public GitHub repository: https://github.com/KarchinLab/bigmhc ref. 41. Scikit-Learn v.1.0.2 was used to calculate performance metrics. Pandas v.1.4.2 and Numpy v.1.21.5 were used for data processing. SAM suite v.3.5 buildmodel and align2model were used to generate multiple sequence alignments. Matplotlib v.3.5.1, Seaborn v.0.12.2, py3Dmol v.2.0.1 and v.AlphaFold2 were used to generate figures.

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Acknowledgements

This work was supported in part by the US National Institutes of Health grant CA121113 to V.A. and R.K., the Department of Defense Congressionally Directed Medical Research Programs grant CA190755 to V.A. and the ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center grant UG1CA233259 to V.A.

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA

    Benjamin Alexander Albert, Yunxiao Yang, Xiaoshan M. Shao & Rachel Karchin

  2. Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA

    Benjamin Alexander Albert, Yunxiao Yang & Rachel Karchin

  3. The Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Dipika Singh, Kellie N. Smith, Valsamo Anagnostou & Rachel Karchin

  4. Bloomberg∼Kimmel Institute for Cancer Immunotherapy, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Dipika Singh, Kellie N. Smith & Valsamo Anagnostou

  5. Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, USA

    Rachel Karchin

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Contributions

B.A.A. and R.K. conceived the study and performed the experiments; Y.Y. contributed to 3D visualizations and model ideas; X.M.S. curated the MANAFEST data; D.S. and K.N.S. collected the MANAFEST dataset; B.A.A. and R.K. wrote the draft manuscript; B.A.A., V.A. and R.K. revised the manuscript; R.K. supervised the research.

Corresponding author

Correspondence to Rachel Karchin.

Ethics declarations

Competing interests

Under a licence agreement between Genentech and the Johns Hopkins University, X.M.S., R.K. and the university are entitled to royalty distributions related to the MHCnuggets technology discussed in this publication. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies. V.A. has received research funding to her institution from Bristol Myers Squibb, AstraZeneca, Personal Genome Diagnostics and Delfi Diagnostics in the past 5 years. V.A. is an inventor on patent applications (63/276,525, 17/779,936, 16/312,152, 16/341,862, 17/047,006 and 17/598,690) submitted by Johns Hopkins University related to cancer genomic analyses, ctDNA therapeutic response monitoring and immunogenomic features of response to immunotherapy that have been licensed to one or more entities. Under the terms of these licence agreements, the university and inventors are entitled to fees and royalty distributions. The remaining authors declare no competing interests.

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Nature Machine Intelligence thanks Reid F. Thompson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Visualization of BigMHC average attention to MHC encodings on the EL test data.

a Heatmap visualization of the average attention value for each position in the MHC pseudosequence on the EL testing dataset. The heatmap is stratified by MHC allele as rows, and separated by positive and negative testing instances. The position of each amino acid in the sequences from IPD-IMGT/HLA is provided at the bottom of each column. Darker values indicate MHC positions that are more influential on the final model output. The column of Differences depicts the Negatives values subtracted from the Positives values; thus, darker blue colours are most correctly discriminative whereas darker red attention values in this column highlight erroneous inferences. b Overlays of the Differences column from the training dataset on the MHC molecule using py3Dmol. MHC protein structure models are generated using AlphaFold.

Extended Data Fig. 2 Visualization of the average MHC attention on the EL training data.

Heatmap visualization method of Extended Data Fig. 1a applied to the EL training data.

Extended Data Fig. 3 Neoepitope immunogenicity prediction results stratified by neoepitope length.

PPVn, mean PPVn, AUROC, and AUPRC are calculated and visualized in the same manner as Fig. 4. Bars represent means and error bars are 95% CIs. Neoepitope prediction performance from Fig. 4 is stratified by neoepitope length: 8 (n = 184), 9 (n = 281), 10 (n = 241), and 11 (n = 231).

Extended Data Fig. 4 IEDB infectious disease antigen immunogenicity prediction results stratified by epitope length.

PPVn, mean PPVn, AUROC, and AUPRC are calculated and visualized in the same manner as Fig. 4. Bars represent means and error bars are 95% CIs. Infectious disease antigen prediction performance from Fig. 4 is stratified by epitope length: 8 (n = 112), 9 (n = 1486), 10 (n = 555), and 11 (n = 192).

Extended Data Fig. 5 Composition of all training and evaluation datasets.

Positive and negative instances were stratified by HLA loci in the first two columns and by epitope length in the latter two columns. Positives in the EL datasets are detected by mass spectrometry, whereas negatives in the EL datasets are decoys. Both positives and negatives in the immunogenicity datasets are experimentally validated by immunogenicity assays.

Supplementary information

Supplementary Information

Supplementary discussion and Tables 1–4.

Reporting Summary

Supplementary Table 5

Results of all user-facing tools on all EL data, including training, validation and testing data.

Source data

Source Data Fig. 1

AUROC and AUPRC stratified by MHC and by MHC and epitope length for all evaluated methods on the EL test data.

Source Data Fig. 2

Mean PPVn, AUROC and AUPRC for all methods on the two immunogenicity test sets.

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Albert, B.A., Yang, Y., Shao, X.M. et al. Deep neural networks predict class I major histocompatibility complex epitope presentation and transfer learn neoepitope immunogenicity. Nat Mach Intell 5, 861–872 (2023). https://doi.org/10.1038/s42256-023-00694-6

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