High efficacy of a Listeria-based vaccine against metastatic breast cancer reveals a dual mode of action

Hee Kim Sun, Francisco Castro, Yvonne Paterson, Claudia Gravekamp

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Most cancer vaccines induce CTL responses to tumor-associated antigens (TAA). Killing of tumor cells occurs through TAA-specific CTL-mediated cytolysis. Here, we show that one preventive followed by two therapeutic immunizations with an attenuated Listeria monocytogenes (LM)-based vaccine eradicates all metastases and almost the entire primary tumor in the syngeneic, aggressive mouse breast tumor model 4T1. We provide strong evidence that this is due to the combined result of direct kill by Listeria infecting the tumor cells and by CTL responses against Listeria antigens. We showed by electron microscopy that LM expressing truncated listeriolysin O (LLO) and amino acid fragments 311 to 660 of TAA Mage-b (LM-LLO-Mage-b311-660) and the control strain LM-LLO infect tumor cells in vitro and in vivo. In vitro data indicate that tumor cell death occurs through activation of NADP+ oxidase and increased intracellular Ca2+ levels, both resulting in the production of high ROS levels. Because both LM-LLO and LM-LLO-Mage-b 311-660 showed equally strong efficacies in vivo, we concluded that LM-LLO was crucial and Mage-b was of less importance. We found strong CTL responses to LM-LLO in the spleen, and depletion of CD8 T cells in vivo resulted in significant tumor regrowth (52%) in LM-LLO-vaccinated mice, indicating that LM-LLO-specific CTL indeed partially contributed to tumor cell kill in vivo. This dual mode of action of a Listeria-based vaccine has not been described before and may provide new directions in the development of more effective vaccines against metastatic breast cancer.

Original languageEnglish (US)
Pages (from-to)5860-5866
Number of pages7
JournalCancer Research
Volume69
Issue number14
DOIs
StatePublished - Jul 15 2009

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Listeria
Listeria monocytogenes
Vaccines
Breast Neoplasms
Neoplasm Antigens
Neoplasms
Listeria monocytogenes hlyA protein
Cancer Vaccines
NADP
Immunization
Electron Microscopy
Oxidoreductases
Cell Death
Spleen
Neoplasm Metastasis
T-Lymphocytes
Antigens
Amino Acids

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

High efficacy of a Listeria-based vaccine against metastatic breast cancer reveals a dual mode of action. / Sun, Hee Kim; Castro, Francisco; Paterson, Yvonne; Gravekamp, Claudia.

In: Cancer Research, Vol. 69, No. 14, 15.07.2009, p. 5860-5866.

Research output: Contribution to journalArticle

Sun, Hee Kim ; Castro, Francisco ; Paterson, Yvonne ; Gravekamp, Claudia. / High efficacy of a Listeria-based vaccine against metastatic breast cancer reveals a dual mode of action. In: Cancer Research. 2009 ; Vol. 69, No. 14. pp. 5860-5866.
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