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Signal sequence deletion and fusion to tetanus toxoid epitope augment antitumor immune responses to a human carcinoembryonic antigen (CEA) plasmid DNA vaccine in a murine test system

Cancer Gene Therapy volume 10, pages 365–376 (2003)Cite this article

Abstract

Carcinoembryonic antigen (CEA, CEACAM5) is expressed on several human carcinomas including colon cancer. CEA contains signal peptides that target the protein through the endoplasmic reticulum and to the cell membrane. We constructed a plasmid DNA vaccine encoding a truncated CEA (ΔCEA), devoid of its signal peptides, and demonstrated that it was retained inside the cell, while full-length CEA (wtCEA) was expressed on the membrane. We hypothesized that intracellular retention of ΔCEA would enhance MHC class I presentation of CEA peptides, thus favoring cellular immune responses. In addition, a promiscuous T-helper epitope (Q830-L844 of tetanus toxoid) was fused to the N-terminal of the truncated CEA gene (tetΔCEA). C57BL/6 mice immunized with DNA encoding wtCEA or tetΔCEA developed both humoral and cellular immune responses to CEA. SCID mice transplanted with spleen cells from tetΔCEA but not wtCEA-immunized C57BL/6 mice showed strong suppression of tumor growth after inoculation of human CEA-expressing colon carcinoma cells. Immune spleen cell populations depleted for either B, T or both B and T cells were active, indicating that effector cells might also reside in other populations. The present approach to manipulating antigen presentation may open new possibilities for immunotherapy against colon and other CEA-secreting carcinomas.

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Acknowledgements

We thank Sten Hammarström for generous gifts of purified native CEA and N Beauchemin for the p91023(B) plasmid. This work was supported by grants from Cancerföreningen in Stockholm, the Swedish Medical Research Council and the Swedish Medical Society.

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Authors and Affiliations

  1. Karolinska Institutet, Microbiology and Tumor Biology Center, Box 280, Stockholm, SE-171 77, Sweden

    Lars H Lund, Karolina Andersson, Bartek Zuber, Anneli Karlsson, Gunnel Engström, Jorma Hinkula, Britta Wahren & Gösta Winberg

  2. Swedish Institute for Infectious Disease Control, Solna, 171 82, Sweden

    Lars H Lund, Karolina Andersson, Bartek Zuber, Anneli Karlsson, Gunnel Engström, Jorma Hinkula, Britta Wahren & Gösta Winberg

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Lund, L., Andersson, K., Zuber, B. et al. Signal sequence deletion and fusion to tetanus toxoid epitope augment antitumor immune responses to a human carcinoembryonic antigen (CEA) plasmid DNA vaccine in a murine test system. Cancer Gene Ther 10, 365–376 (2003). https://doi.org/10.1038/sj.cgt.7700574

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