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Plasmid DNA vaccine encoding prostatic acid phosphatase is effective in eliciting autologous antigen-specific CD8+ T cells

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Abstract

Prostatic acid phosphatase (PAP) is a prostate cancer tumor antigen and a prostate-specific protein shared by rats and humans. Previous studies indicated that Copenhagen rats immunized with a recombinant vaccinia virus expressing human PAP (hPAP) developed PAP-specific cytotoxic T cells (CTL) with cross reactivity to rat PAP (rPAP) and evidence of prostate inflammation. Viral delivery of vaccine antigens is an active area of clinical investigation. However, a potential difficulty with viral-based immunizations is that immune responses elicited to the viral vector might limit the possibility of multiple immunizations. In this paper, we investigate the ability of another genetic immunization method, a DNA vaccine encoding PAP, to elicit antigen-specific CD8+ T cell immune responses. Specifically, Lewis rats were immunized with either a plasmid DNA-based (pTVG-HP) or vaccinia-based (VV-HP) vaccine each encoding hPAP. We determined that rats immunized with a DNA vaccine encoding hPAP developed a Th1-biased immune response as indicated by proliferating PAP-specific CD4+ and CD8+ cells and IFNγ production. Rats immunized with vaccinia virus encoding PAP did not develop a PAP-specific response unless boosted with a heterologous vaccination scheme. Most importantly, multiple immunizations with a DNA vaccine encoding the rat PAP homologue (pTVG-RP) could overcome peripheral self-tolerance against rPAP and generate a Th1-biased antigen-specific CD4+ and CD8+ T cell response. Overall, DNA vaccines provide a safe and effective method of generating prostate antigen-specific T cell responses. These findings support the investigation of PAP-specific DNA vaccines in human clinical trials.

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Abbreviations

BrdU:

Bromodeoxyuridine

BSA:

Bovine serum albumin

CFA:

Complete Freund’s adjuvant

CTL:

Cytotoxic T lymphocytes

DC:

Dendritic cell

EDTA:

Ethylenediaminetetraacetic acid

ELISA:

Enzyme-linked immunosorbent assay

GFP:

Green fluorescent protein

GM-CSF:

Granulocyte macrophage colony-stimulating factor

hPAP:

Human prostatic acid phosphatase

IFA:

Incomplete Freund’s adjuvant

IFNγ:

Interferon-gamma

IgG:

Immunoglobulin G

IL-10:

Interleukin-10

MHC:

Major histocompatibility complex

MOI:

Multiplicity of infection

OD:

Optical density

PAP:

Prostatic acid phosphatase

PBS:

Phosphate buffered saline

pfu:

Plaque-forming unit

PHA:

Phytohemaglutinin

pTVG-HP:

DNA vaccine encoding hPAP

pTVG-RP:

DNA vaccine encoding rPAP

rPAP:

Rat prostatic acid phosphatase

SE:

Standard error

TMB:

Tetramethylbenzidine

VV-HP:

Recombinant vaccinia virus encoding hPAP

VVwt:

Wild type vaccinia virus

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Acknowledgments

This work is supported for L.E.J. by the DOD Prostate Cancer Research Program (W81XWH-04-1-0256) and for D.G.M. by NIH (K23 RR16489) and the DOD Prostate Cancer Research Program (DAMD17-03-1-0050).

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Authors and Affiliations

  1. Department of Medicine, University of Wisconsin, Madison, WI, 53792, USA

    Laura E. Johnson, Thomas P. Frye & Douglas G. McNeel

  2. Vince Lombardi Gene Therapy Laboratory, Immunotherapy Program, St. Luke’s Medical Center, Milwaukee, WI, 53215, USA

    Nachimuthu Chinnasamy & Dhanalakshmi Chinnasamy

  3. K4/518 Clinical Science Center, 600 Highland Avenue, Madison, WI, 53792, USA

    Douglas G. McNeel

Authors
  1. Laura E. Johnson
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  2. Thomas P. Frye
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  3. Nachimuthu Chinnasamy
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  5. Douglas G. McNeel
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Correspondence to Douglas G. McNeel.

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Johnson, L.E., Frye, T.P., Chinnasamy, N. et al. Plasmid DNA vaccine encoding prostatic acid phosphatase is effective in eliciting autologous antigen-specific CD8+ T cells. Cancer Immunol Immunother 56, 885–895 (2007). https://doi.org/10.1007/s00262-006-0241-8

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