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.
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Authors | Zhisong Chen, Laurent Ozbun, Namju Chong, Anu Wallecha, Jay A Berzofsky, Samir N Khleif |
Journal | Cancer immunology research
(Cancer Immunol Res)
Vol. 2
Issue 9
Pg. 911-22
(Sep 2014)
ISSN: 2326-6074 [Electronic] United States |
PMID | 24872025
(Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
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Copyright | ©2014 American Association for Cancer Research. |
Chemical References |
- Cancer Vaccines
- Papillomavirus E7 Proteins
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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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