High-throughput prediction of MHC Class i and II neoantigens with MH cnuggets

Xiaoshan M. Shao, Rohit Bhattacharya, Justin Huang, I. K.Ashok Sivakumar, Collin Tokheim, Lily Zheng, Dylan Hirsch, Benjamin Kaminow, Ashton Omdahl, Maria Bonsack, Angelika B. Riemer, Victor E. Velculescu, Valsamo Anagnostou, Kymberleigh A. Pagel, Rachel Karchin

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Computational prediction of binding between neoantigen peptides and major histocompatibility complex (MHC) proteins can be used to predict patient response to cancer immunotherapy. Current neoantigen predictors focus on in silico estimation of MHCbinding affinity and are limited by low predictive value for actual peptide presentation, inadequate support for rare MHC alleles, and poor scalability to high-throughput data sets. To address these limitations, we developed MHCnuggets, a deep neural network method that predicts peptide-MHC binding. MHCnuggets can predict binding for common or rare alleles of MHC class I or II with a single neural network architecture. Using a long short-term memory network (LSTM), MHCnuggets accepts peptides of variable length and is faster than other methods. When compared with methods that integrate binding affinity and MHC-bound peptide (HLAp) data from mass spectrometry, MHCnuggets yields a 4-fold increase in positive predictive value on independent HLAp data.We applied MHCnuggets to 26 cancer types in The Cancer Genome Atlas, processing 26.3 million allele-peptide comparisons in under 2.3 hours, yielding 101,326 unique predicted immunogenic missense mutations (IMM). Predicted IMM hotspots occurred in 38 genes, including 24 driver genes. Predicted IMM load was significantly associated with increased immune cell infiltration (P < 2 ×10-16), including CD8 T cells. Only 0.16% of predicted IMMs were observed in more than 2 patients, with 61.7% of these derived from driver mutations. Thus, we describe a method for neoantigen prediction and its performance characteristics and demonstrate its utility in data sets representing multiple human cancers.

Original languageEnglish (US)
Pages (from-to)396-408
Number of pages13
JournalCancer Immunology Research
Volume8
Issue number3
DOIs
StatePublished - Mar 1 2020

ASJC Scopus subject areas

  • General Medicine

Fingerprint

Dive into the research topics of 'High-throughput prediction of MHC Class i and II neoantigens with MH cnuggets'. Together they form a unique fingerprint.

Cite this