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Cancers 2019, 11(2), 266; https://doi.org/10.3390/cancers11020266

Identification of Novel HLA Class II-Restricted Neoantigens Derived from Driver Mutations

1
Department of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa 241-8515, Japan
2
Research & Early Development Division, BrightPath Biotherapeutics Co., Ltd., 3-25-22 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-0821, Japan
3
Department of Innovative Cancer Immunotherapy, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
4
Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
*
Author to whom correspondence should be addressed.
Received: 31 January 2019 / Revised: 18 February 2019 / Accepted: 20 February 2019 / Published: 24 February 2019
(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)
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Abstract

Neoantigens derived from tumor-specific genetic mutations might be suitable targets for cancer immunotherapy because of their high immunogenicity. In the current study, we evaluated the immunogenicity of 10 driver mutations that are frequently expressed in various cancers using peripheral blood mononuclear cells from healthy donors (n = 25). Of the 10 synthetic peptides (27-mer) derived from these mutations, the six peptides from KRAS-G12D, KRAS-G12R, KRAS-G13D, NRAS-Q61R, PIK3CA-H1047R, and C-Kit-D816V induced T cell responses, suggesting that frequent driver mutations are not always less immunogenic. In particular, immune responses to PIK3CA-H1047R, C-Kit-D816V, KRAS-G13D, and NRAS-Q61R were observed in more than 10% of the donors. All six peptides induced human leukocyte antigen (HLA) class II-restricted CD4+ T cell responses; notably, PIK3CA-H1047R contained at least two different CD4+ T cell epitopes restricted to different HLA class II alleles. In addition, PIK3CA-H1047R and C-Kit-D816V induced antigen-specific CD8+ T cells as well, indicating that they might contain both HLA class I- and class II-restricted epitopes. Since the identified neoantigens might be shared by patients with various types of cancers and are not easily lost due to immune escape, they have the potential to be promising off-the-shelf cancer immunotherapy targets in patients with the corresponding mutations. View Full-Text
Keywords: neoantigen; driver mutation; MHC class II epitope neoantigen; driver mutation; MHC class II epitope
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Iiizumi, S.; Ohtake, J.; Murakami, N.; Kouro, T.; Kawahara, M.; Isoda, F.; Hamana, H.; Kishi, H.; Nakamura, N.; Sasada, T. Identification of Novel HLA Class II-Restricted Neoantigens Derived from Driver Mutations. Cancers 2019, 11, 266.

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