Multiple myeloma, gammopathies

Identification and characterization of HLA-A24-specific XBP1, CD138 (Syndecan-1) and CS1 (SLAMF7) peptides inducing antigens-specific memory cytotoxic T lymphocytes targeting multiple myeloma

Abstract

X-box binding protein 1 (XBP1), CD138 (Syndecan-1) and CS1 (SLAMF7) are highly expressed antigens in cancers including multiple myeloma (MM). Here, we identify and characterize immunogenic HLA-A24 peptides derived from these antigens for potential vaccination therapy of HLA-A24+ patients with MM. The identified immunogenic HLA-A24-specific XBP1 unspliced (UN)185–193 (I S P W I L A V L), XBP1 spliced (SP)223–231 (V Y P E G P S S L), CD138265–273 (I F A V C L V G F) and CS1240–248 (L F V L G L F L W) peptides induced antigen-specific CTL with anti-MM activity in an HLA-A24 restricted manner. Furthermore, a cocktail containing the four HLA-A24 peptides evoked MM-specific CTL with distinct phenotypic profiles (CD28, CD40L, 41BB, CD38, CD69) and anti-tumor activities, evidenced by perforin upregulation, CD107a degranulation (cytotoxicity) and Th1-type cytokines (IFN-γ/IL-2/TNF-α) production in response to HLA-A24+ MM cells. The multipeptide-specific CTL included antigen-specific memory CD8+ T cells expressing both T-cell activation (CD38, CD69) and immune checkpoints antigens (CTLA, PD-1, LAG-3, TIM-3). These results provide the framework for a multipeptide vaccination therapy to induce tumor-specific CTL in HLA-A24-positive patients with myeloma and other cancers expressing these antigens.

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Acknowledgements

The authors acknowledge the generous gift of T2-A*2401 cells from Dr Y Miyahara at Mie University School of Medicine (Mie, Japan) and Dr E Jaffee at the Johns Hopkins University School of Medicine (Baltimore). We also thank Mr John Daley and Ms Suzan Lazo-Kallanian from the flow cytometry facility at Dana-Farber Cancer Institute for providing flow cytometry assistance. This work was supported in part by grants from the National Institutes of Health Grants RO1-124929 to Dr Nikhil C Munshi, P50-100007, PO1-78378 and PO1155258 to Drs Kenneth C Anderson and Nikhil C Munshi, and RO1-50947 to Dr Kenneth C Anderson. Dr Kenneth C Anderson is an American Cancer Society Clinical Research Professor.

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Correspondence to J Bae.

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NC Munshi is an honorarium of Celgene, Millennium and Novartis; KC Anderson is an honorarium of Celgene, Millennium and Onyx; and PGR Richardson is an honorarium of Celgene, Millennium and Johnson & Johnson. NC Munshi, KC Anderson and J Bae have ownership interest and are advisory board members in OncoPep Inc. The remaining authors declare no conflict of interest.

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Bae, J., Hideshima, T., Zhang, G. et al. Identification and characterization of HLA-A24-specific XBP1, CD138 (Syndecan-1) and CS1 (SLAMF7) peptides inducing antigens-specific memory cytotoxic T lymphocytes targeting multiple myeloma. Leukemia 32, 752–764 (2018). https://doi.org/10.1038/leu.2017.316

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