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Immunotherapy

Two unique HLA-A*0201 restricted peptides derived from cyclin E as immunotherapeutic targets in leukemia

Leukemia volume 34, pages 1626–1636 (2020)Cite this article

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Abstract

Immunotherapy targeting leukemia-associated antigens has shown promising results. Because of the heterogeneity of leukemia, vaccines with a single peptide have elicited only a limited immune response. Targeting several peptides together elicited peptide-specific cytotoxic T lymphocytes (CTLs) in leukemia patients, and this was associated with clinical responses. Thus, the discovery of novel antigens is essential. In the current study, we investigated cyclin E as a novel target for immunotherapy. Cyclin E1 and cyclin E2 were found to be highly expressed in hematologic malignancies, according to reverse transcription polymerase chain reaction and western blot analysis. We identified two HLA-A*0201 binding nonameric peptides, CCNE1M from cyclin E1 and CCNE2L from cyclin E2, which both elicited the peptide-specific CTLs. The peptide-specific CTLs specifically kill leukemia cells. Furthermore, CCNE1M and CCNE2L CTLs were increased in leukemia patients who underwent allogeneic hematopoietic stem cell transplantation, and this was associated with desired clinical outcomes. Our findings suggest that cyclin E1 and cyclin E2 are potential targets for immunotherapy in leukemia.

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Fig. 1: Cyclin E1 and cyclin E2 were overexpressed in leukemia cells.
Fig. 2: Two peptides derived from cyclin E bind HLA-A*0201 with high affinity.
Fig. 3: CCNE1M and CCNE2L peptides elicit peptide-specific CTLs from healthy donors.
Fig. 4: Specific cytotoxicity of CCNE1M- and CCNE2L-CTLs.
Fig. 5: High frequency of CCNE1M-CTL and CCNE2L-CTL in post allo-SCT leukemia patients.
Fig. 6: CCNE1- and CCNE2-CTLs from AML patients after allo-SCT are functional.

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Acknowledgements

This study was supported by research funding from NCI CA100632 (to JJM); NCI CA148600 (to JJM); Leukemia and Lymphoma Society 6030-12 (to JJM); P30 CA16672 (to KCD); Leukemia and Lymphoma Society 7262-08 (to JJM). The manuscript was edited by Department of Scientific Publications at M.D. Anderson Cancer Center.

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  1. These authors are contributed equally: Hong He, Yukio Kondo, and Ken Ishiyama

Authors and Affiliations

  1. Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    Hong He, Gheath Alatrash, Sijie Lu, Kathryn Cox, Na Qiao, Karen Clise-Dwyer, Lisa St. John, Pariya Sukhumalchandra, Qing Ma & Jeffrey J. Molldrem

  2. Department of Internal Medicine, Toyama Prefectural Central Hospital, Toyama, Japan

    Yukio Kondo

  3. Department of Hematology, Kanazawa University Hospital, Kanazawa, Japan

    Ken Ishiyama

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Contributions

Authorship statement: HH, YK, KI, SL, KC, NQ, KCD, and PS performed experiments and analyzed data. GA, LSJ, and QM wrote the paper. JJM designed the research and wrote the paper.

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Correspondence to Jeffrey J. Molldrem.

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He, H., Kondo, Y., Ishiyama, K. et al. Two unique HLA-A*0201 restricted peptides derived from cyclin E as immunotherapeutic targets in leukemia. Leukemia 34, 1626–1636 (2020). https://doi.org/10.1038/s41375-019-0698-z

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