Abstract
The advent of tyrosine kinase inhibitor (TKI) therapy markedly improved the outcome of patients with chronic-phase chronic myeloid leukemia (CML). However, the poor prognosis of patients with advanced-phase CML and the lifelong dependency on TKIs are remaining challenges; therefore, an effective therapeutic has been sought. The BCR–ABL p210 fusion protein’s junction region represents a leukemia-specific neoantigen and is thus an attractive target for antigen-specific T-cell immunotherapy. BCR–ABL p210 fusion-region-specific CD4+ T-helper (Th) cells possess antileukemic potential, but their function remains unclear. In this study, we established a BCR–ABL p210 b3a2 fusion-region-specific CD4+ Th-cell clone (b3a2-specific Th clone) and examined its dendritic cell (DC)-mediated antileukemic potential. The b3a2-specific Th clone recognized the b3a2 peptide in the context of HLA-DRB1*09:01 and exhibited a Th1 profile. Activation of this clone through T-cell antigen receptor stimulation triggered DC maturation, as indicated by upregulated production of CD86 and IL-12p70 by DCs, which depended on CD40 ligation by CD40L expressed on b3a2-specific Th cells. Moreover, in the presence of HLA-A*24:02-restricted Wilms tumor 1 (WT1)235–243 peptide, DCs conditioned by b3a2-specific Th cells efficiently stimulated the primary expansion of WTI-specific cytotoxic T lymphocytes (CTLs). The expanded CTLs were cytotoxic toward WT1235–243-peptide-loaded HLA-A*24:02-positive cell lines and exerted a potent antileukemic effect in vivo. However, the b3a2-specific Th-clone-mediated antileukemic CTL responses were strongly inhibited by both TKIs and interferon-α. Our findings indicate a crucial role of b3a2-specific Th cells in leukemia antigen-specific CTL-mediated immunity and provide an experimental basis for establishing novel CML immunotherapies.
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Acknowledgements
CSII-EF, pCMV-VSV-G-RSV-Rev and pCAG-HIVgp were kindly provided by Dr H Miyoshi (RIKEN BioResource Center, Tsukuba, Japan). The cDNA encoding HLA-DRB1*09:01 (DR9) was kindly provided by Dr H Kobayashi (Asahikawa Medical College, Asahikawa, Japan). This study was performed as a research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-DIRECT), Ministry of Education, Culture, Sports, Science and Technology of Japan. This study was supported by grants from Nagono Medical Foundation, the National Cancer Center Research and Development Fund (25-A-7) and the Takeda Science Foundation.
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Shin Kaneko is a founder, shareholder and scientific adviser at AsTlym Co., Ltd. Hitoshi Kiyoi received research funding from Bristol-Myers Squibb, Chugai Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Zenyaku Kogyo and Fujifilm Corporation. The remaining authors declare no conflict of interest.
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Ueda, N., Zhang, R., Tatsumi, M. et al. BCR–ABL-specific CD4+ T-helper cells promote the priming of antigen-specific cytotoxic T cells via dendritic cells. Cell Mol Immunol 15, 15–26 (2018). https://doi.org/10.1038/cmi.2016.7
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DOI: https://doi.org/10.1038/cmi.2016.7
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