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CD8+ T cells, NK cells and IFN-γ are important for control of tumor with downregulated MHC class I expression by DNA vaccination

Gene Therapy volume 10, pages 1311–1320 (2003)Cite this article

Abstract

One of the major hurdles facing cancer immunotherapy is that cancers may downregulate expression of MHC class I molecules. The development of a suitable tumor model with downregulated MHC class I expression is critical for designing vaccines and immunotherapeutic strategies to control such tumors. We developed an E7-expressing murine tumor model with downregulated MHC class I expression, TC-1 P3 (A15). Using this model, we tested DNA and vaccinia vaccines for their ability to control tumors with downregulated MHC class I expression. We found that vaccination with DNA encoding E7 linked to Mycobacterial heat shock protein 70 (HSP70) generated a significant antitumor effect against TC-1 P3 (A15), while vaccination with E7/HSP70 vaccinia did not generate an appreciable antitumor effect. Lymphocyte depletion experiments revealed that both CD8+ T cells and NK cells were essential for the antitumor effect generated by E7/HSP70 DNA against TC-1 P3 (A15). Furthermore, tumor protection experiments using IFN-γ knockout mice revealed that IFN-γ was essential for the antitumor effect generated by E7/HSP70 DNA against TC-1 P3 (A15). Our results demonstrate that vaccination with E7/HSP70 DNA results in a significant antitumor effect against a neoplasm with downregulated MHC class I expression and the importance of CD8+ T cells, NK cells, and IFN-γ in generating this antitumor effect.

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Acknowledgements

We thank Drs Robert Kurman, Drew Pardoll, and Hyam Levitsky for helpful discussions. We also thank Drs Richard Roden and Ralph Hruban for a critical review of the manuscript. We thank The Tetramer Core Facility at NIH for providing PE-labeled E7 (aa 49–57) peptide-H2-Db tetramer. Dr Wen-Fang Cheng (RE88P005) is a recipient of the NHRI physician scientist fellowship award. Dr Cheng is supported by National Science Committee of Taiwan (NSC91-2341-B-002-369) and National Taiwan University Hospital (NTUH 91-F002). Ken-Yu Lin is a Howard Hughes predoctoral fellow.

This work was supported by NIH 5 PO1 34582-01, U19 CA72108-02, RO1 CA72631-01, RO1 CA83706-01, PO1AI48203-01, and American Cancer Society.

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  1. W F Cheng and C F Hung: W-F Cheng and C-F Hung contributed equally to this paper

Authors and Affiliations

  1. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    W F Cheng, C F Hung, K Y Lin, M Ling, J Juang, L He, C T Lin & T-C Wu

  2. Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan

    W F Cheng

  3. Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei, Taiwan

    C T Lin

  4. Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    T-C Wu

  5. Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    T-C Wu

  6. Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    T-C Wu

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Cheng, W., Hung, C., Lin, K. et al. CD8+ T cells, NK cells and IFN-γ are important for control of tumor with downregulated MHC class I expression by DNA vaccination. Gene Ther 10, 1311–1320 (2003). https://doi.org/10.1038/sj.gt.3301982

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