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

Zhisong Chen, Laurent Ozbun, Namju Chong, Anu Wallecha, Jay A. Berzofsky, Samir N. Khleif

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)911-922
Number of pages12
JournalCancer Immunology Research
Volume2
Issue number9
DOIs
StatePublished - Sep 1 2014

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Listeria monocytogenes
Vaccines
T-Lymphocytes
Papillomaviridae
Listeria monocytogenes hlyA protein
Combined Vaccines
Neoplasms
Phagosomes
Proteins
Adoptive Transfer
Regulatory T-Lymphocytes
Bacteria

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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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. / Chen, Zhisong; Ozbun, Laurent; Chong, Namju; Wallecha, Anu; Berzofsky, Jay A.; Khleif, Samir N.

In: Cancer Immunology Research, Vol. 2, No. 9, 01.09.2014, p. 911-922.

Research output: Contribution to journalArticle

Chen, Zhisong ; Ozbun, Laurent ; Chong, Namju ; Wallecha, Anu ; Berzofsky, Jay A. ; Khleif, Samir N. / 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. In: Cancer Immunology Research. 2014 ; Vol. 2, No. 9. pp. 911-922.
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AU - Berzofsky, Jay A.

AU - Khleif, Samir N.

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