Cancer Immunology, Immunotherapy

, Volume 57, Issue 9, pp 1391–1398 | Cite as

Danger signals and nonself entity of tumor antigen are both required for eliciting effective immune responses against HER-2/neu positive mammary carcinoma: implications for vaccine design

  • Maciej Kmieciak
  • Johanna K. Morales
  • Joshua Morales
  • Elizabeth Bolesta
  • Margaret Grimes
  • Masoud H. Manjili
Original Article

Abstract

Using parental FVB mice and their neu transgenic counterparts, FVBN202, we showed for the first time that dangerous hyperplasia of mammary epithelial cells coincided with breaking immunological tolerance to the neu “self” tumor antigen, though such immune responses failed to prevent formation of spontaneous neu-overexpressing mammary carcinoma (MMC) or reject transplanted MMC in FVBN202 mice. On the other hand, neu-specific immune responses appeared to be effective against MMC in parental FVB mice because of the fact that rat neu protein was seen as “nonself” antigen in these animals and the protein was dangerously overexpressed in MMC. Interestingly, low/intermediate expression of the neu “nonself” protein in tumors induced immune responses but such immune responses failed to reject the tumor in FVB mice. Our results showed that self–nonself (SNS) entity of a tumor antigen or danger signal alone, while may equally induce an antigen-specific immune response, will not warrant the efficacy of immune responses against tumors. On the other hand, entity of antigen in the context of dangerous conditions, i.e. abnormal/dangerous overexpression of the neu nonself protein, will warrant effective anti-tumor immune responses in FVB mice. This unified “danger-SNS” model suggests focusing on identification of naturally processed cryptic or mutated epitopes, which are considered semi-nonself by the host immune system, along with novel dangerous adjuvant in vaccine design.

Keywords

HER-2/neu Breast cancer Danger signal 

Notes

Acknowledgments

This work was supported by the NIH R01 CA104757 grant (MHM) and flow cytometry shared resources facility, supported in part by the NIH grant P30CA16059. We gratefully acknowledge the support of VCU Massey Cancer Center and the Commonwealth Foundation for Cancer Research. We greatly appreciate Laura Graham in assisting us with adoptive T cell therapy. We thank Hooman Nikizad, Frances White and Julie S. Farnsworth for their assistance with flow cytometry. We also thank Dr. John Subjeck of Roswell Park Cancer Institute for providing us with the HSP110 expression vectors.

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Maciej Kmieciak
    • 1
  • Johanna K. Morales
    • 1
  • Joshua Morales
    • 1
  • Elizabeth Bolesta
    • 1
  • Margaret Grimes
    • 2
  • Masoud H. Manjili
    • 1
  1. 1.Department of Microbiology and ImmunologyVCU School of Medicine, Massey Cancer CenterRichmondUSA
  2. 2.Department of PathologyVCU School of Medicine, Massey Cancer CenterRichmondUSA

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