Studies have shown that a regulatory T cell (Treg) cell decrease accompanied complete regression of tumor growth induced by a Listeria monocytogenes (Lm)-based vaccine expressing a fusion protein consisting of truncated listeriolysin O (LLO) and human papilloma virus (HPV) E7 protein (Lm-LLO-E7). However, how Lm-based vaccine causes Treg decrease remains unclear yet. Using a highly attenuated Lm dal dat ∆actA strain (LmddA)-based vaccine, we report here that the vector LmddA itself was sufficient to induce a decrease in the proportion of Treg cells 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 decreasing Treg frequency to a lower degree. While adoptive transfer of Tregs compromised the anti-tumor efficacy of 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 Lm recombinant replacing LLO with perfringolysin O (PFO), allowing exit from the phagolysosome but without LLO, confirmed that the adjuvant effect was dependent on LLO itself. These results suggest that LLO may serve as a promising adjuvant by preferentially inducing CD4+FoxP3- T cell and CD8+ T cell expansion, thus improving the ratio of Tregs to CD4+FoxP3- T cells and to CD8+ T cells and favoring immune responses to eradicate tumor.
- Received November 8, 2013.
- Revision received April 22, 2014.
- Accepted May 12, 2014.
- Copyright © 2014, American Association for Cancer Research.