Translational Therapeutics

An effective peptide vaccine strategy circumventing clonal MHC heterogeneity of murine myeloid leukaemia

Abstract

Background

Therapeutic cancer vaccines are an attractive approach for treating malignant tumours, and successful tumour eradication depends primarily on controlling tumour immunosuppression status as well as heterogeneity of tumour cells driven by epigenetic alterations.

Methods

Peptide-loaded dendritic cell (DC) prime and non-infectious peptide booster heterologous immunisations were assessed for the immunogenicity of polo-like kinase-1 (PLK1)-derived peptides. Heterologous vaccination regimen targeting multiple shared tumour antigens simultaneously with PD-L1 blockade was assessed against murine myeloid leukaemia.

Results

A synthetic PLK1122 (DSDFVFVVL)-based heterologous vaccination generated large numbers of long-lasting antigen-specific CD8 T-cells eliciting therapeutic effects against various established tumours. The therapeutic efficacy of single antigen-targeting PLK1122-based vaccine with sufficient endurance of PD-L1 blockade toward C1498 leukaemia relied on the heterogeneous clonal levels of MHC-I and PD-L1 expression. A novel multi-peptide-based vaccination targeting PLK1 and survivin simultaneously along with PD1 blockade led to complete tumour eradication and long-term survival in mice with clonally heterologous C1498 myeloid leukaemia.

Conclusions

Our findings suggest that PLK1 could be an attractive immunotherapeutic target antigen for cancer immunotherapy, and that similar strategies would be applicable for the optimisation of cancer vaccines for the treatment of numerous viral diseases and malignant tumours.

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Fig. 1: Immunisation with PLK1 peptides induces CD8 T-cell responses resulting in potent anti-tumour immunity.
Fig. 2: Therapeutic anti-tumour effects of PLK1122DC_TriVax vaccination against murine C1498 leukaemia.
Fig. 3: PD-L1 blockade enhance the therapeutic efficacy of PLK1122DC_TriVax vaccination against murine C1498 leukaemia.
Fig. 4: PLK1122DC_TriVax immunisation with PD-L1 blockade induces long-lasting CD8 T-cell responses capable of eradicating homogenous C1498Homo-luc leukaemia.
Fig. 5: Multi-antigenic peptide vaccine comprising PLK1122 and Sur20 induces concurrent CD8 T-cell responses capable of enhancing the therapeutic anti-tumour efficacy with PD-L1 blockade.
Fig. 6: DCs priming followed by TriVax boost with multi-peptides with sustained PD-L1 blockade elicits augmented therapeutic effectiveness overcoming clonal heterogeneity of C1498 leukaemia.

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Affiliations

Authors

Contributions

A.R.S. designed and performed the experiments, analysed the data, and wrote the paper. S.E.L. and H.C. contributed to perform the experiments. H.J.S. contributed to data analysis. H.I.C. and T.G.K. contributed to experimental design, data analysis, and paper writing for all studies.

Corresponding authors

Correspondence to Hyun-Il Cho or Tai-Gyu Kim.

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Ethics approval and consent to participate

All experiments were performed in accordance with relevant guidelines and regulations of Central Research Ethics Committee of the Catholic University of Korea. Animal experiments were approved by and performed in compliance with the guidelines and regulations by Institutional Animal Care and Use Committee (IACUC, protocol #CUMS-2019-0169-03) of the Catholic University of Korea. All participants consented to partake in the study. This study was performed in accordance with the Declaration of Helsinki. All cell lines used in the experiment were purchased from the American Type Culture Collection (ATCC).

Data availability

Summarised primary research data are presented in the paper. No publicly available dataset has been generated as part of this work.

Competing interests

The authors declare no competing interests.

Funding information

This research was supported by a grant of the Korean Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI15C1748).

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Shin, A., Lee, S., Choi, H. et al. An effective peptide vaccine strategy circumventing clonal MHC heterogeneity of murine myeloid leukaemia. Br J Cancer (2020). https://doi.org/10.1038/s41416-020-0955-y

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