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Quantitative T-cell repertoire analysis of peripheral blood mononuclear cells from lung cancer patients following long-term cancer peptide vaccination

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Abstract

Therapeutic cancer peptide vaccination is an immunotherapy designed to elicit cytotoxic T-lymphocyte (CTL) responses in patients. A number of therapeutic vaccination trials have been performed, nevertheless there are only a few reports that have analyzed the T-cell receptors (TCRs) expressed on tumor antigen-specific CTLs. Here, we use next-generation sequencing (NGS) to analyze TCRs of vaccine-induced CTL clones and the TCR repertoire of bulk T cells in peripheral blood mononuclear cells (PBMCs) from two lung cancer patients over the course of long-term vaccine therapy. In both patients, vaccination with two epitope peptides derived from cancer/testis antigens (upregulated lung cancer 10 (URLC10) and cell division associated 1 (CDCA1)) induced specific CTLs expressing various TCRs. All URLC10-specific CTL clones tested showed Ca2+ influx, IFN-γ production, and cytotoxicity when co-cultured with URLC10-pulsed tumor cells. Moreover, in CTL clones that were not stained with the URLC10/MHC-multimer, the CD3 ζ chain was not phosphorylated. NGS of the TCR repertoire of bulk PBMCs demonstrated that the frequency of vaccine peptide-specific CTL clones was near the minimum detectable threshold level. These results demonstrate that vaccination induces antigen-specific CTLs expressing various TCRs at different time points in cancer patients, and that some CTL clones are maintained in PBMCs during long-term treatment, including some with TCRs that do not bind peptide/MHC-multimer.

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Abbreviations

CDCA1:

Cell division associated 1

CDCA1-64:

CDCA1-derived HLA-A24 (A*24:02)-restricted peptide

CDCA1/MHC-multimer:

CDCA1-64/ HLA-A*24:02 pentamer-PE

CMV pp65 peptide:

CMV-derived HLA-A24 (A*24:02)-restricted peptide

HIV epitope peptide:

HIV-derived HLA-A24 (A*24:02)-restricted peptide

NGS:

Next-generation sequencing

TC:

Treatment course

URLC10:

Upregulated lung cancer 10

URLC10-177:

URLC10-derived HLA-A24 (A*24:02)-restricted peptide

URLC10/MHC-multimer:

URLC10-177/ HLA-A*24:02 tetramer-PE

VEGFR:

Vascular endothelial growth factor receptor

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Acknowledgements

We are grateful to OncoTherapy Science, Inc. (Kanagawa, Japan) for their technical support.

Funding

This work was supported by the Ministry of Education, Science, and Culture, Japan (15K14410) to K. Takeda.

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Authors and Affiliations

  1. Division of Cell Biology, Biomedical Research Center, Graduate School of Medicine, Juntendo University, Hongo 2-1-1, Bunkyo-ku, Tokyo, 113-8421, Japan

    Kazuyoshi Takeda

  2. Department of Biofunctional Micribiota, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, 113-8421, Japan

    Kazuyoshi Takeda & Ko Okumura

  3. Department of Rheumatology and Clinical Immunology, Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, National Hospital Organization, Sagamihara, Kanagawa, 252-0392, Japan

    Kazutaka Kitaura & Ryuji Suzuki

  4. Department of Chest Surgery, School of Medicine, Fukushima Medical University, Fukushima, 960-1295, Japan

    Yuki Owada, Satoshi Muto, Naoyuki Okabe, Takeo Hasegawa, Jun Osugi, Mika Hoshino & Hiroyuki Suzuki

  5. Department of Clinical Immuno-oncology, Showa University, Setagaya-ku, Tokyo, 157-8577, Japan

    Takuya Tsunoda

  6. Atopy (Allergy) Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, 113-8421, Japan

    Ko Okumura

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  1. Kazuyoshi Takeda
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  2. Kazutaka Kitaura
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Contributions

Kazuyoshi Takeda designed this study, interpreted the data, and wrote the manuscript. Kazutaka Kitaura and Ryuji Suzuki carried out next-generation sequencing. Yuki Owada, Satoshi Muto, Naoyuki Okabe, Takeo Hasegawa, Jun Osugi, and Mika Hoshino carried out biological analysis. Takuya Tsunoda, Ko Okumura and Hiroyuki Suzuki revised the manuscript. All authors had final approval of the submitted and published versions.

Corresponding author

Correspondence to Kazuyoshi Takeda.

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Conflict of interest

K. Kitaura and R. Suzuki are currently employed by Repertoire Genesis, Inc. The other authors declare that they have no conflicts of interest.

Ethical approval and ethical standards

This study was approved by the ethical committee of Fukushima Medical University (approval number: 810) and was registered with ClinicalTrials.gov (NCT00874588). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any animal studies performed by any of the authors.

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Informed consent was obtained from all individual participants included in the study.

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Takeda, K., Kitaura, K., Suzuki, R. et al. Quantitative T-cell repertoire analysis of peripheral blood mononuclear cells from lung cancer patients following long-term cancer peptide vaccination. Cancer Immunol Immunother 67, 949–964 (2018). https://doi.org/10.1007/s00262-018-2152-x

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