Neo-intline: integrated pipeline enables neoantigen design through the in-silico presentation of T-cell epitope

Abstract

Neoantigen vaccines are one of the most effective immunotherapies for personalized tumour treatment. The current immunogen design of neoantigen vaccines is usually based on whole-genome sequencing (WGS) and bioinformatics prediction that focuses on the prediction of binding affinity between peptide and MHC molecules, ignoring other peptide-presenting related steps. This may result in a gap between high prediction accuracy and relatively low clinical effectiveness. In this study, we designed an integrated in-silico pipeline, Neo-intline, which started from the SNPs and indels of the tumour samples to simulate the presentation process of peptides in-vivo through an integrated calculation model. Validation on the benchmark dataset of TESLA and clinically validated neoantigens illustrated that neo-intline could outperform current state-of-the-art tools on both sample level and melanoma level. Furthermore, by taking the mouse melanoma model as an example, we verified the effectiveness of 20 neoantigens, including 10 MHC-I and 10 MHC-II peptides. The in-vitro and in-vivo experiments showed that both peptides predicted by Neo-intline could recruit corresponding CD4+ T cells and CD8+ T cells to induce a T-cell-mediated cellular immune response. Moreover, although the therapeutic effect of neoantigen vaccines alone is not sufficient, combinations with other specific therapies, such as broad-spectrum immune-enhanced adjuvants of granulocyte-macrophage colony-stimulating factor (GM-CSF) and polyinosinic-polycytidylic acid (poly(I:C)), or immune checkpoint inhibitors, such as PD-1/PD-L1 antibodies, can illustrate significant anticancer effects on melanoma. Neo-intline can be used as a benchmark process for the design and screening of immunogenic targets for neoantigen vaccines.

CD8+ T cell-based cancer immunotherapy

“…Neoantigen vaccine may not stand alone to effectively diminish malignant tumors. Its combinations with other therapeutics, such as immune-enhanced adjuvants of granulocyte-macrophage colony-stimulating factor (GM-CSF) or ICIs, can enhance their anticancer effects on solid tumors [ 111 ]. For instance, a triple therapy combining neoantigen vaccine that induces the accumulation of CD8 + T cells, anti-PD-1 that suppresses immune tolerance signals, and agonist antibody against OX40 that induces T cell memory, was invented to treat mice bearing pancreatic adenocarcinoma of low immunogenicity and poor T cell infiltration, where neoantigen vaccine significantly increased tumor responsiveness [ 112 ].…”