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Treatment with an immature dendritic cell-targeting vaccine supplemented with IFN-α and an inhibitor of DNA methylation markedly enhances survival in a murine melanoma model

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Abstract

Background

The chemokine MIP-3α (CCL20) binds to CCR6 on immature dendritic cells. DNA vaccines fusing MIP-3α to melanoma-associated antigens have shown improved efficacy and immunogenicity in the B16F10 mouse melanoma model. Here, we report that the combination of type-I interferon therapy (IFNα) with 5-Aza-2′-deoxycitidine (5Aza) profoundly enhanced the therapeutic efficacy of a MIP-3α-Gp100-Trp2 DNA vaccine.

Methods

Beginning on day 5 post-transplantation of B16F10 melanoma, vaccine was administered intramuscularly (i.m.) by electroporation. CpG adjuvant was given 2 days later. 5Aza was given intraperitoneally at 1 mg/kg and IFNα therapy either intratumorally or i.m. as noted. Tumor sizes, tumor growth, and mouse survival were assessed. Tumor lysate gene expression levels and tumor-infiltrating lymphocytes (TILs) were assessed by qRT-PCR and flow cytometry, respectively.

Results

Adding IFNα and 5Aza treatments to mice vaccinated with MIP-3α-Gp100-Trp2 leads to reduced tumor burden and increased median survival (39% over vaccine and 95% over controls). Tumor lysate expression of CCL19 and CCR7 were upregulated ten and fivefold over vaccine, respectively. Vaccine-specific and overall CD8+ TILs were increased over vaccine (sevenfold and fourfold, respectively), as well as the proportion of TILs that were CD8+ (twofold).

Conclusions

Efficient targeting of antigen to immature dendritic cells with a chemokine-fusion vaccine offers an alternative to classic and dendritic cell vaccines. Combining this approach with IFNα and 5Aza treatment significantly improved vaccine efficacy. This improved efficacy correlated with changes in chemokine gene expression and CD8+ TIL infiltration and was dependent on the presence of all therapeutic components.

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Abbreviations

5Aza:

5-Aza-2′-Deoxycytidine

D-MIP3α:

Defective version of MIP3α

i.t.:

Intra-tumoral administration

iDC:

Immature dendritic cells

IFNα or IFN:

Interferon alpha

MGp100:

Vaccine fusing MIP-3α to antigenic region of Gp100

MGpTrp2:

Vaccine fusing MIP-3α to antigenic regions of Gp100 and Trp2

MIP-3α:

Macrophage inflammatory protein-3 alpha

MTrp2:

Vaccine fusing MIP-3α to antigenic region of Trp2

TIL:

Tumor infiltrating lymphocyte

Trp2:

Tyrosinase-related protein 2

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Acknowledgements

We would like to acknowledge Dr. TC Wu (Johns Hopkins School of Medicine, Baltimore, MD) for allowing us to utilize his electroporator and Dr. Jonathan Schneck (Johns Hopkins School of Medicine, Baltimore, MD) for his gift of B16F10 cells. We would also like to acknowledge Dr. Prakash Srinivisan (Johns Hopkins Bloomberg School of Public Health (JHBSPH), Baltimore, MD) for flow cytometry support. We would finally like to acknowledge the Molecular Microbiology and Immunology Common Equipment Core Facility and specifically Anne Jedlicka (JHBSPH, Baltimore, MD) for flow cytometry and qRT-PCR support.

Funding

This research was supported by philanthropic donations to the Markham laboratory.

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Authors and Affiliations

  1. The W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD, 21205, USA

    James T. Gordy, Kun Luo & Richard B. Markham

  2. Department of Medicine, Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Aakanksha Kapoor, Emily S. Kim, Samuel K. Ayeh & Petros C. Karakousis

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  1. James T. Gordy
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Contributions

JTG: performed, designed, and analyzed all the experiments and was the primary author of the manuscript. KL: provided assistance with design and implementation of the mouse studies. ESK, AK, and SKA: provided assistance with the qRT-PCR studies and the revision process. PCK: contributed to the revision process. RBM: contributed to the conception, design, analysis of data, and the writing of the manuscript. All authors read and approved the final manuscript version.

Corresponding author

Correspondence to Richard B. Markham.

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Conflict of interest

James T. Gordy and Richard B. Markham are inventors on pending patents using the vaccine platform described in this paper and have equity interest in a company that has rights to this vaccine platform. The authors declare that there is no other conflict of interest.

Ethical approval and ethical standards

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the IACUC of the Johns Hopkins University under Protocols #MO16H147 and MO19H139. This article does not contain any studies with human participants performed by any of the authors

Informed consent

Not applicable.

Animal source

5–6 week old female C57BL/6 (H-2b) mice were purchased from Charles River Laboratories (Wilmington, MA).

Cell line authentication

Low-passage B16F10 cells were gifted to us by Dr. Jonathan Schneck (Johns Hopkins School of Medicine, Baltimore, MD). Cells were maintained with low passage stocks to maintain uniformity in transplantation, and therefore further authentication was deemed unnecessary.

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Versions of this work have been published as an online pre-print and as conference abstracts Pre-print: bioRxiv 531616; https://doi.org/10.1101/531616 [1].

American Association for Cancer Research Annual Meeting, April 15th, 2018, Chicago, IL, USA [2].

Society for the Immunotherapy of Cancer 33rd Annual Meeting, November 7–11, 2018, Washington, DC, USA [3].

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Gordy, J.T., Luo, K., Kapoor, A. et al. Treatment with an immature dendritic cell-targeting vaccine supplemented with IFN-α and an inhibitor of DNA methylation markedly enhances survival in a murine melanoma model. Cancer Immunol Immunother 69, 569–580 (2020). https://doi.org/10.1007/s00262-019-02471-0

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