The Ability of Two Listeria monocytogenes Vaccines Targeting Human Papillomavirus-16 E7 to Induce an Antitumor Response Correlates with Myeloid Dendritic Cell Function

Abstract

Previous work from our laboratory has shown that Lm-LLO-E7 induces complete regression of ∼75% of established TC-1 tumors, whereas Lm-E7 only slows the growth of such tumors. In this study, we examine the effects of Lm-LLO-E7 vs Lm-E7 on APCs. We hypothesize that the difference in antitumor efficacy of the two vaccines is due to the ability of each of these vectors to render immature dendritic cells (DCs) effective APCs in terms of MHC class II or costimulatory molecule expression. We also examine the ability of these vectors to stimulate cytokine production by DCs. Both vectors induced IL-12 and TNF-α, but only Lm-LLO-E7 induced IL-2 production by DCs. Lm-LLO-E7 also induced significantly higher levels of MHC class II molecules, CD40, and B7 costimulatory molecules (CD86, B7-H1, and B7-DC) on DCs than Lm-E7. Interestingly, a shift of CD11c+ cells from CD86low to CD86high is observed post-Lm-LLO-E7 infection. A similar shift is also observed for B7-H1 and B7-DC molecules. Moreover, Lm-LLO-E7, but not Lm-E7-pulsed DCs, stimulate naive T cell proliferation. These results indicate that Lm-LLO-E7 is more effective than Lm-E7 at inducing DC maturation. This effect is independent of the E7 Ag, because Lm-LLO-NP, and a mixture of Lm-LLO-NP and Lm-E7 induce the same changes in DC phenotype as Lm-LLO-E7. Taken together, the changes in DC expression correlate well with the differences in antitumor efficacy between these two vaccines.

Listeria monocytogenes-Derived Listeriolysin O Has Pathogen-Associated Molecular Pattern-Like Properties Independent of Its Hemolytic Ability

“…Thus, our evidence suggests that dtLLO acts in a PAMP-like manner to stimulate production of the proinflammatory cytokines IL-12 and TNF-␣, as well as to facilitate DC maturation. This is consistent with the previous finding that L. monocytogenes-based vaccines expressing the LLO fusion protein Lm-LLO-E7 cause rapid and effective phenotypic and functional maturation of myeloid DCs (27). The enhancement of DC maturation by LLO likely induces higher levels of in vitro T cell proliferation and in vivo antitumor immunity.…”

Fusion to Listeriolysin O and Delivery by Listeria monocytogenes Enhances the Immunogenicity of HER-2/neu and Reveals Subdominant Epitopes in the FVB/N Mouse

“…However, even fusing the Ag to a LLO molecule from which the PEST sequence has been deleted resulted in better antitumor efficacy than using the Ag alone, suggesting that LLO may have an adjuvant effect quite apart from enhancing Ag processing. We have shown previously using vaccines that deliver the HPV-16 E7 Ag that Lm-LLO-E7 can mature bone marrow-derived dendritic cells and up-regulate costimulatory molecules, whereas Lm-E7 does not, which also points to an adjuvant effect for LLO (33).…”

Listeria monocytogenes

“…94 In DCs, Lm induces the release of IL-2; IL-6; IL-12; and TNF-α, as well as the subsequent upregulation of other proteins (e.g., CD40, PD-L1) that promote the maturation and activation of high-affinity T cells. 59,95 The adaptive immune response against Lm infection serves 2 main functions: the specific lysis of infected cells and the rapid secretion of IFN-γ in response to innate production of IL-12 and IL-18. 96,97 IFN-γ is a crucial contributor to the cell-mediated immune response via macrophage activation; the increasing of antigen presentation via the MHC class I and II pathways; and the inhibition of Th2 cell expansion.…”