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Episomal expression of truncated listeriolysin O in LmddA-LLO-E7 vaccine enhances antitumor efficacy by preferentially inducing expansions of CD4+FoxP3- and CD8+ T cells.

Abstract
Studies have shown that Listeria monocytogenes (Lm)-based vaccine expressing a fusion protein comprising truncated listeriolysin O (LLO) and human papilloma virus (HPV) E7 protein (Lm-LLO-E7) induces a decrease in regulatory T cells (Treg) and complete regression of established, transplanted HPV-TC-1 tumors in mice. However, how the Lm-based vaccine causes a decrease in Tregs remains unclear. Using a highly attenuated Lm dal dat ΔactA strain (LmddA)-based vaccine, we report here that the vector LmddA was sufficient to induce a decrease in the proportion of Tregs by preferentially expanding CD4(+)FoxP3(-) T cells and CD8(+) T cells by a mechanism dependent on and directly mediated by LLO. Episomal expression of a nonhemolytic truncated LLO in Lm (LmddA-LLO) significantly augmented the expansion, thus further decreasing Treg frequency. Although adoptive transfer of Tregs compromised the antitumor efficacy of the LmddA-LLO-E7 vaccine, a combination of LmddA-LLO and an Lm-based vaccine expressing E7 protein (Lm-E7) induced complete regression against established TC-1 tumors. An engineered LLO-minus Lm expressing perfringolysin O (PFO) that enables the recombinant bacteria to exit from the phagolysosome without LLO confirmed that the adjuvant effect was dependent on LLO. These results suggest that LLO may serve as a promising adjuvant by preferentially inducing the expansions of CD4(+)FoxP3(-) T cells and CD8(+) T cells, thus reducing the ratio of Tregs to CD4(+)FoxP3(-) T cells and to CD8(+) T cells favoring immune responses to eradicate tumor.
AuthorsZhisong Chen, Laurent Ozbun, Namju Chong, Anu Wallecha, Jay A Berzofsky, Samir N Khleif
JournalCancer immunology research (Cancer Immunol Res) Vol. 2 Issue 9 Pg. 911-22 (Sep 2014) ISSN: 2326-6074 [Electronic] United States
PMID24872025 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
Copyright©2014 American Association for Cancer Research.
Chemical References
  • Cancer Vaccines
  • Papillomavirus E7 Proteins
Topics
  • Adoptive Transfer
  • Animals
  • CD8-Positive T-Lymphocytes (immunology)
  • Cancer Vaccines (therapeutic use)
  • Cell Line, Tumor
  • Female
  • Genetic Vectors
  • Listeria monocytogenes (genetics)
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms, Experimental (therapy)
  • Papillomavirus E7 Proteins (genetics)
  • Plasmids (genetics)
  • T-Lymphocytes, Cytotoxic (immunology)
  • T-Lymphocytes, Regulatory (immunology)

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