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Murine mammary adenocarcinoma cells transfected with p53 and/or Flt3L induce antitumor immune responses

Cancer Gene Therapy volume 12, pages 427–437 (2005)Cite this article

Abstract

Transfection of tumors with tumor-associated antigens (Ags) or cytokines can increase immunogenicity and slow down tumor growth. However, the effect of cotransfection with genes that encode a tumor-associated Ag, such as the tumor suppressor gene p53, and a cytokine has been rarely investigated. We report that transfection of 4T1 mammary tumor cells (p53-null) with the dendritic cell (DC) growth factor, fms-like tyrosine kinase 3 ligand (Flt3L), significantly delayed their growth in vivo, resulting in the rejection of 100% of the tumors formed by injection of tumor cells cotransfected with Flt3L and p53. Immunization with irradiated 4T1 cells transfected with Flt3L induced DC infiltration of the immunization site and significantly increased the antitumor T-cell responses. Further, immunization with irradiated 4T1 cells cotransfected with p53 and Flt3L significantly increased p53-specific immune responses, as compared to vaccination with 4T1 cells transfected with either Flt3L or p53 alone. These responses included increased activity against clone 66 (Cl-66), a sister tumor to 4T1 with high murine mutant p53 expression levels. Challenge with Cl-66 revealed that immunization with irradiated 4T1-Flt3L-p53 cells significantly slowed growth, prolonged survival, and resulted in complete remissions. Further, immunization with irradiated 4T1-Flt3L also slowed Cl-66 growth, although to a lesser extent than 4T1-Flt3L-p53. We suggest that immunization with DCs transfected with the Flt3L transgene and a tumor Ag may potentially heighten T-cell responses and therapeutic activity.

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Acknowledgements

We thank Michelle Varney, Aihua Li, and Matthew Backora for their assistance with the experiments and Richard Murcek, Lisa Chudomelka, Tina Winekauf, and Kirsten Stites for assisting with the preparation of the manuscript. This research was supported by the Nebraska Research Initiative Programs in Gene Therapy (JET) and in Molecular Therapeutics (JET, RKS, and JCS), by an LB595/Cattlemen's Ball Grant (JCS), and by an International Exchange Award from the National Science Foundation and by the Department of Health, People's Republic of China (HS).

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Authors and Affiliations

  1. International Joint Cancer Institute of Shanghai and Institute of Orthopaedics, Xijing Hospital, Xi'an, 710032, P.R. China

    Hongxun Sang

  2. Laboratory of Transplantation Immunology, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA

    Hongxun Sang, Vladimir M Pisarev, Jennifer Chavez, Simon Robinson, Lori Hatcher, Corey Munger, Cathy B Talmadge, Joyce C Solheim, Rakesh K Singh & James E Talmadge

  3. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA

    Vladimir M Pisarev, Yajun Guo, Joyce C Solheim & James E Talmadge

  4. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA

    Joyce C Solheim

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Sang, H., Pisarev, V., Chavez, J. et al. Murine mammary adenocarcinoma cells transfected with p53 and/or Flt3L induce antitumor immune responses. Cancer Gene Ther 12, 427–437 (2005). https://doi.org/10.1038/sj.cgt.7700809

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