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Identification of mouse helper epitopes for WT1-specific CD4+ T cells

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Abstract

Helper T lymphocytes (HTLs) play a central role in cancer immunity because they can not only help the induction and proliferation of cytotoxic T lymphocytes (CTLs) but also their differentiation into cytotoxic CD4+ T cells and directly kill the target cells.This study describes the identification of three novel mouse Th epitope peptides, WT135-52, WT186-102 and WT1294-312, derived from WT1 protein, which is the most potent tumor-associated antigen. Compared to immunization with WT1 CTL peptide alone, immunization with the addition of these WT1-specific Th peptides strongly induced WT1-specific CTLs, continued to maintain them, and efficiently rejected the challenge of WT1-expressing tumor cells. Importantly, the majority of WT1-specific CTLs induced by the co-immunization with WT1 CTL and the WT1-specific Th peptides were CD44+CD62L− effector memory CD8+ T cells, which played a central role in tumor rejection. Establishment of mouse models suitable for the analysis of the detailed mechanism of these functions of HTLs is very important. These results clearly showed that WT1-specific HTLs perform an essential function in WT1-specific tumor immunity. Therefore, the WT1-specific Th peptides identified here should make a major contribution to elucidation of the mutual roles of WT1-specific CTLs and HTLs in cancer immunity in in vivo mouse models.

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Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

FlowJo, PRID:SCR_008520.

Abbreviations

CTLs:

Cytotoxic T lymphocytes

HTLs:

Helper T lymphocytes

SPF:

Specific pathogen-free

TAA:

Tumor-associated antigen

TCR:

T cell receptor

WT1:

Wilms’ tumor gene 1

i.d.:

Intradermally

s.c.:

Subcutaneously

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Funding

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 JP19K16863.

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Authors and Affiliations

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

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

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

    Jun Nakata, Kanako Imafuku, Hiromu Hayashibara, Kazuki Isokawa & Yusuke Oji

  3. Department of Immunology, School of Medicine, Kochi University, Kochi, Japan

    Keiko Udaka

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

    Soyoko Morimoto, Yoshiko Hashii & Akihiro Tsuboi

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

    Naoki Hosen

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

    Sumiyuki Nishida & Yoshihiro Oka

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

    Yoshihiro Oka

  8. Department of Immunopathology, WPI, Immunology Frontier Research Center (iFReC), 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. Hiroko Nakajima
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Contributions

Conception and design by HN, JN, YO, KU and HS. Acquisition of data by HN, JN, KI, HH, and KI. Analysis and interpretation of data by HN, JN, YO, SS, FF, SM, AT, YO and HS. Investigation by KH, NH, YH, SN and YO. Writing, review, and/or revision of the manuscript by HN, JN, YO and HS. Study supervision by HS.

Corresponding author

Correspondence to Hiroko Nakajima.

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

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All animal experiments were performed with the approval of the Animal Experiment Committee of Osaka University.

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This paper is not a clinical trial study and is not applicable.

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Nakajima, H., Nakata, J., Imafuku, K. et al. Identification of mouse helper epitopes for WT1-specific CD4+ T cells. Cancer Immunol Immunother 70, 3323–3335 (2021). https://doi.org/10.1007/s00262-021-03003-5

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