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Secretion of stress protein grp170 promotes immune-mediated inhibition of murine prostate tumor

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Abstract

It is well established that certain stress proteins or molecular chaperones are highly efficient in cross-presenting tumor-derived antigens, resulting in a potent antitumor immune response. In this study we demonstrate that genetic modification of weakly immunogenic murine prostate tumor cells (TRAMP-C2) by stable transfection with a secretable form of endoplasmic reticulum resident chaperone grp170 significantly enhances its immunogenicity in vivo. Generation of systemic antitumor immunity is indicated by the growth suppression of distant parental tumors, which is associated with increased tumor infiltration, elevated effector functions of CD8+ T-cells. Immunization with inactivated grp170-secreting C2 cells augments a CD8+ T-cell dependent, tumor-protective effect. Furthermore, infection of C2 tumor cells with a nonreplicating adenoviral vectors encoding secretable grp170 promotes tumor immunogenicity more effectively than plasmid transduction, as shown by the increased production of pro-inflammatory cytokine TNF-α by dendritice cells and enhanced therapeutic efficacy in treating pre-established tumors. Given a repertoire of undefined antigens in prostate tumor, manipulation of cellular compartmentalization of immuno-stimulatory chaperone grp170 to elicit systemic tumor immunity may be used to improve treatment outcomes for prostate cancer when combined with other treatment modalities.

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Acknowledgments

This work was supported by National Cancer Institute (NCI) Grant CA121848, CA129111, American Cancer Society Grant RSG-08-187-01-LIB, Roswell Park Alliance Foundation, and NCI Cancer Center Support Grant to the Roswell Park Cancer Institute CA016056.

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Authors and Affiliations

  1. Department of Cellular Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Ping Gao, Xiaolei Sun, Xing Chen, John Subjeck & Xiang-Yang Wang

  2. Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Beijing Normal University, 100875, Beijing, China

    Ping Gao

  3. Department of Urologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Xiang-Yang Wang

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  1. Ping Gao
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  2. Xiaolei Sun
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  4. John Subjeck
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Correspondence to Xiang-Yang Wang.

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Gao, P., Sun, X., Chen, X. et al. Secretion of stress protein grp170 promotes immune-mediated inhibition of murine prostate tumor. Cancer Immunol Immunother 58, 1319–1328 (2009). https://doi.org/10.1007/s00262-008-0647-6

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  • DOI: https://doi.org/10.1007/s00262-008-0647-6

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