TY - JOUR
T1 - Role of in silico structural modeling in predicting immunogenic neoepitopes for cancer vaccine development
AU - Zaidi, Neeha
AU - Soban, Mariya
AU - Chen, Fangluo
AU - Kinkead, Heather
AU - Mathew, Jocelyn
AU - Yarchoan, Mark
AU - Armstrong, Todd D.
AU - Haider, Shozeb
AU - Jaffee, Elizabeth M.
N1 - Funding Information:
The authors gratefully acknowledge the James W. and Frances Gibson McGlothlin Foundation; The Skip Viragh Center for Pancreatic Cancer at Johns Hopkins; The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins; The Lustgarten Foundation for Pancreatic Cancer Research; and a Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant (SU2C-AACR-DT1414 to EMJ). NZ was the recipient of the ASCO Young Investigator Award, the GI SPORE Career Enhancement Award, and the Linda Rubin Fellowship for Pancreatic Cancer Research and Patient Care.
Funding Information:
consultant for Adaptive Biotech, CTSONE, Achilles, DrangonFly, and Genocea. She receives funding from Lustgarten Foundation and AduroBiotech and through a licensing agreement between AduroBiotech and Johns Hopkins University (JHU), and JHU has the potential to receive royalties on GVAX. She is the Chief Medical Advisor for Lustgarten and serves on the National Cancer Advisory Board and as an Advisor to the Parker Institute for Cancer Immunotherapy (PICI). MY serves on the Advisory Board for AstraZeneca, Eisai, Exelixis, and Geneos. He also receives grant/research support from Bristol-Myer Squibb, Exelixis, Genentech/Roche, and Incyte.
Publisher Copyright:
© 2020, Zaidi et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2020/9/3
Y1 - 2020/9/3
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.136991
DO - 10.1172/jci.insight.136991
M3 - Article
C2 - 32879142
AN - SCOPUS:85090261899
VL - 5
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 17
M1 - e136991
ER -