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Intravaginal TLR agonists increase local vaccine-specific CD8 T cells and human papillomavirus-associated
S Domingos-Pereira1, L Decrausaz, L Derré
1Department of Urology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
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 (IVAG) instillation of CpG-ODN (TLR9 agonist) or poly-(I:C) (TLR3 agonist) after subcutaneous E7 vaccination increased ~fivefold the number of vaccine-specific interferon-γ-secreting CD8 T cells in the genital mucosa (GM) of mice, without affecting the E7-specific systemic response. The IVAG 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 IVAG CpG-ODN or poly-(I:C) was mediated by TLR9 and TLR3/melanoma differentiation-associated gene 5 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, IVAG 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.
Insights
Intravaginal immune stimulation with CpG-ODN or poly-(I:C) after vaccination significantly boosts CD8 T cells in the genital tract, enhancing HPV tumor regression in mice.
Area of Science:
- Immunology
- Oncology
- Vaccinology
Background:
- Cervical cancer, often caused by human papillomaviruses (HPV), is a major global health concern for women.
- Current HPV E6/E7 oncogene-specific vaccines show limited clinical success.
Purpose of the Study:
- To investigate if intravaginal (IVAG) administration of immune-stimulating molecules can enhance the efficacy of subcutaneous HPV vaccination.
- To determine the impact of IVAG CpG-ODN and poly-(I:C) on T cell responses in the genital mucosa.
Main Methods:
- Mice were vaccinated subcutaneously with E7 antigen.
- Following vaccination, mice received intravaginal (IVAG) instillation of CpG-ODN (TLR9 agonist) or poly-(I:C) (TLR3 agonist).
- Immune cell populations, cytokine secretion (interferon-γ), chemokine receptor expression, and tumor regression were analyzed.
Main Results:
- IVAG CpG-ODN or poly-(I:C) increased vaccine-specific CD8 T cells in the genital mucosa by approximately fivefold, without altering systemic responses.
- This mucosal treatment selectively recruited CD8 T cells, mediated by TLR9 and TLR3/MDA5 pathways.
- IVAG CpG-ODN significantly improved complete tumor regression rates (75% vs. 20% with vaccination alone).
Conclusions:
- Intravaginal application of immunostimulatory molecules can selectively enhance CD8 T cell responses in the genital mucosa.
- This mucosal immune-boosting strategy holds promise for increasing the effectiveness of parenteral vaccines against HPV-related cancers.
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