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. Cancer Immunol Res; 2(9); 1–12. ©2014 AACR.
Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).
- Received November 8, 2013.
- Revision received April 22, 2014.
- Accepted May 12, 2014.
- ©2014 American Association for Cancer Research.