Intravaginal TLR agonists increase local vaccine-specific CD8 T cells and human papillomavirus-associated genital-tumor regression in mice

Abstract

Human papillomaviruses (HPV)-related cervical cancer is the second leading cause of cancer death in women worldwide. Despite active development, HPV E6/E7 oncogene-specific therapeutic-vaccines have had limited clinical efficacy to date. Here we report that intravaginal instillation of CpG-ODN (TLR9-agonist) or poly-(I:C) (TLR3-agonist) after subcutaneous E7 vaccination increased approximately 5-fold the number of vaccine-specific IFN-γ-secreting CD8 T-cells in the genital mucosa (GM) of mice, without affecting the E7-specific systemic response. The intravaginal treatment locally increased both E7-specific and total CD8 T-cells, but not CD4 T-cells. This previously unreported selective recruitment of CD8 T-cells from the periphery by intravaginal CpG-ODN or poly-(I:C) was mediated by TLR9 and TLR3/Mda5 signaling-pathways, respectively. For CpG, this recruitment was associated with a higher proportion of GM-localized CD8 T-cells expressing both CCR5 and CXCR3 chemokine receptors and E-selectin ligands. Most interestingly, intravaginal CpG-ODN following vaccination led to complete regression of large genital HPV-tumors in 75% of mice, instead of 20% with vaccination alone. These findings suggest that mucosal application of immunostimulatory molecules might substantially increase the effectiveness of parenterally administered vaccines.

LocalSalmonellaimmunostimulation recruits vaccine-specific CD8 T cells and increases regression of bladder tumor

“…This increase is, however, modest compared to the 5-fold increase we previously reported after IVAG CpG. 9 Furthermore, and in contrast to the data obtained in the GM, 9 successive IVES applications of CpG (days 6, 9, and 12) were not able to sustain a higher vaccine-specific CD8 T-cell response in the bladder (see day 15 in Fig. 1B).…”

“…Interestingly, a synergistic effect was observed between local immunostimulation and systemic vaccination with respect to the local recruitment of CD8 T cells; vaccination alone augmented the total number of CD8 T cells in the bladder approximately 3-fold, whereas combination with IVES Ty21a resulted in a 40-fold increase (mean of »2% of total CD8 T cells compared to 0.05% in na€ ıve bladder). In contrast to CpG and PIC, 9 IVES Ty21a also induced a modest 3-fold increase in CD4 T-cells, either alone or following vaccination (Fig. 3A), but once again IVES immunostimulation had no systemic effect ( Table 1).…”

“…[2][3][4][5] An alternative approach, irrespective of the immunization route, is to enhance T-cell attraction to the tumor site through the local application of selected chemokines 6 or Toll-like receptor (TLR) agonists that are able to modify the expression of selectins, integrins, chemokines, and chemokine receptors. 7,8 Along this line, we recently reported that intravaginal (IVAG) administration of CpG (a TLR-9 agonist) resulted in the accumulation of CD8 T cells co-expressing CCR5 and CXCR3 chemokine receptors and E-selectin ligands (ESL), most probably through CpG-induced expression of CCL5, CXCL9, CXCL10, CXCL11, and/or E-selectin 9 . Most importantly, in a murine model of cervical cancer, this strategy resulted in more efficient genital tumor regression than vaccination alone.…”

“…Most importantly, in a murine model of cervical cancer, this strategy resulted in more efficient genital tumor regression than vaccination alone. 9 Moreover, we have also shown that live bacteria, such as Salmonella attenuated vaccine strains, are more potent immunostimulants than CpG for the recruitment of vaccine-specific CD8 T cells to the genital mucosa (GM) of mice. 10 Here, we explore how such therapeutic approaches can be extended to other cancers.…”

Chronic Myelocytic Leukemia (CML) Patient-Derived Dendritic Cells Transfected with Autologous Total RNA Induces CML-Specific Cytotoxicity

“…and CD4? CTLs by targeting different epitopes [25][26][27]. The RNA vaccine is relatively safe owing to a short half-life and low possibility of genome integration.…”