Zaidi, N;
Soban, M;
Chen, F;
Kinkead, H;
Mathew, J;
Yarchoan, M;
Armstrong, TD;
... Jaffee, EM; + view all
(2020)
Role of in silico structural modeling in predicting immunogenic neoepitopes for cancer vaccine development.
JCI Insight
, 5
(17)
, Article e136991. 10.1172/jci.insight.136991.
Preview |
Text
136991.1-20200828073253-covered-253bed37ca4c1ab43d105aefdf7b5536.pdf - Published Version Download (5MB) | Preview |
Abstract
In prior studies, we delineated the landscape of neoantigens arising from nonsynonymous point mutations in a murine pancreatic cancer model, Panc02. We developed a peptide vaccine by targeting neoantigens predicted using a pipeline that incorporates the MHC binding algorithm NetMHC. The vaccine, when combined with immune checkpoint modulators, elicited a robust neoepitope-specific antitumor immune response and led to tumor clearance. However, only a small fraction of the predicted neoepitopes induced T cell immunity, similarly to that reported for neoantigen vaccines tested in clinical studies. While these studies have used binding affinities to MHC I as surrogates for T cell immunity, this approach does not include spatial information on the mutated residue that is crucial for TCR activation. Here, we investigate conformational alterations in and around the MHC binding groove induced by selected minimal neoepitopes, and we examine the influence of a given mutated residue as a function of its spatial position. We found that structural parameters, including the solvent-accessible surface area (SASA) of the neoepitope and the position and spatial configuration of the mutated residue within the sequence, can be used to improve the prediction of immunogenic neoepitopes for inclusion in cancer vaccines.
| Type: | Article |
|---|---|
| Title: | Role of in silico structural modeling in predicting immunogenic neoepitopes for cancer vaccine development |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1172/jci.insight.136991 |
| Publisher version: | https://doi.org/10.1172/jci.insight.136991 |
| Language: | English |
| Additional information: | Copyright © 2020 Zaidi et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10109556 |
Archive Staff Only
 |
View Item |
