HLApollo: A superior transformer model for pan-allelic peptide-MHC-I presentation prediction, with diverse negative coverage, deconvolution and protein language features.
Thrift, W. J.; Lounsbury, N. W.; Broadwell, Q.; Heidersbach, A.; Freund, E.; Phung, Q.; Abdolazimi, Y.; Chen, J.; Capietto, A.-H.; Tong, A.-J.; Rose, C. M.; Blanchette, C.; Lill, J.; Haley, B.; Delamarre, L.; Bourgon, R.; Liu, K.; Jhunjhunwala, S.
Show abstract
Antigen presentation on MHC class I (MHC-I) is key to the adaptive immune response to cancerous cells. Computational prediction of peptide presentation by MHC-I has enabled individualized cancer immunotherapies. Here, we introduce HLApollo, a transformer-based approach with end-to-end modeling of MHC-I sequence, deconvolution, and flanking sequences. To achieve this, we develop a novel training strategy, negative set switching, which greatly reduces overfitting to falsely presumed negatives that are necessarily found in presentation datasets. HLApollo shows a meaningful improvement compared to recent MHC-I models on peptide presentation (20.19% average precision (AP)) and immunogenicity (4.1% AP). As expected, adding gene expression boosts the performance of HLApollo. More interestingly, we show that introduction of features from a protein language model, ESM 1b, remarkably recoups much of the benefits of gene expression in absence of true expression measurements. Finally, we demonstrate excellent pan-allelic generalization, and introduce a framework for estimating the expected accuracy of HLApollo for untrained alleles. This guides the use of HLApollo in a clinical setting, where rare alleles may be observed in some subjects, particularly for underrepresented minorities.
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