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Identification of two distinct populations of WT1-specific cytotoxic T lymphocytes in co-vaccination of WT1 killer and helper peptides

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Abstract

Simultaneous induction of tumor antigen-specific cytotoxic T lymphocytes (CTLs) and helper T lymphocytes (HTLs) is required for an optimal anti-tumor immune response. WT1332, a 16-mer WT1-derived helper peptide, induce HTLs in an HLA class II-restricted manner and enhance the induction of WT1-specific CTLs in vitro. However, in vivo immune reaction to WT1332 vaccination in tumor-bearing patients remained unclear. Here, a striking difference in WT1-specific T cell responses was shown between WT1 CTL + WT1 helper peptide and WT1 CTL peptide vaccines in patients with recurrent glioma. WT1-specific CTLs were more strongly induced in the patients who were immunized with WT1 CTL + WT1 helper peptide vaccine, compared to those who were immunized with WT1 CTL vaccine alone. Importantly, a clear correlation was demonstrated between WT1-specific CTL and WT1332-specific HTL responses. Interestingly, two novel distinct populations of WT1-tetramerlow WT1-TCRlow CD5low and WT1-tetramerhigh WT1-TCRhigh CD5high CTLs were dominantly detected in WT1 CTL + WT1 helper peptide vaccine. Although natural WT1 peptide-reactive CTLs in the latter population were evidently less than those in the former population, the latter population showed natural WT1 peptide-specific proliferation capacity comparable to the former population, suggesting that the latter population highly expressing CD5, a marker of resistance to activation-induced cell death, should strongly expand and persist for a long time in patients. These results demonstrated the advantage of WT1 helper peptide vaccine for the enhancement of WT1-specific CTL induction by WT1 CTL peptide vaccine.

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Abbreviations

APC:

Allophycocyanin

7-AAD:

7-Amino-Actinomycin D

FITC:

Fluorescein isothiocyanate

HLA:

Human Leukocyte Antigen

IL:

Interleukin

IFN:

Interferon

PE:

Phycoerythrin

TCR:

T cell receptor

TNF:

Tumor Necrosis Factor

TAP:

Transporter associated with Antigen Processing

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Precis

WT1 killer + helper peptide vaccine-induced greater WT1-specific CTL response than WT1 killer peptide vaccine in recurrent glioma patients, thereby revealing the existence of two distinct populations, WT1-tetramerhigh TCRhigh CD5high and WT1-tetramerlow TCRlow CD5low T-cells.

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Authors and Affiliations

  1. Department of Cancer Immunology, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Fumihiro Fujiki, Hiroko Nakajima, Kana Hasegawa, Shinji Sogo & Haruo Sugiyama

  2. Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Osaka, Japan

    Akihiro Tsuboi & Soyoko Morimoto

  3. Department of Neurosurgery, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan

    Naoya Hashimoto

  4. Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Osaka, Japan

    Miki Inatome, Jun Nakata & Yusuke Oji

  5. Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan

    Sumiyuki Nishida & Yoshihiro Oka

  6. Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan

    Naoki Hosen

  7. Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan

    Naoki Hosen & Yoshihiro Oka

  8. Department of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan

    Yoshihiro Oka

  9. Immunology Research Unit, Department of Medical Innovations, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan

    Shinji Sogo

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  1. Fumihiro Fujiki
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  2. Akihiro Tsuboi
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Contributions

FF and HS organized this study and prepared this manuscript. AK and NH recruited the patients, carried out the clinical investigations and collected patients’ clinical data. FF, SM, and MI performed the experiments. HN, JN, SN, KH, NH, YoO, and YuO contributed to the acquisition of the patient samples and conception of the study. SS supported this study and gave useful suggestions.

Corresponding author

Correspondence to Fumihiro Fujiki.

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Financial disclosure

Department of Cancer Immunology is a department in collaboration with Otsuka Pharmaceutical Co., Ltd. and is supported with a grant from the company. This study was, in part, supported by JSPS KAKENHI Grant Number JP17K07215.

Conflict of interest

Shinji Sogo is an employee of Otsuka Pharmaceutical Co., Ltd.

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Fujiki, F., Tsuboi, A., Morimoto, S. et al. Identification of two distinct populations of WT1-specific cytotoxic T lymphocytes in co-vaccination of WT1 killer and helper peptides. Cancer Immunol Immunother 70, 253–263 (2021). https://doi.org/10.1007/s00262-020-02675-9

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