Structurally-optimised HPV16 E7/E6 mRNA-LPP mediates dose-sparing efficacy via tumour microenvironment reprogramming.

Area of Science:

• Immunology
• Oncology
• Vaccine Technology

Background:

• Therapeutic vaccines for human papillomavirus (HPV)-associated cancers face challenges from immunosuppressive tumor microenvironments.
• Existing delivery platforms have limited efficacy against HPV-driven malignancies.

Purpose of the Study:

• To compare two mRNA vaccine strategies, non-replicating mRNA (nr-mRNA) and self-amplifying mRNA (sa-mRNA), delivered via a lipopolyplex (LPP) system.
• To evaluate their efficacy in an HPV-driven cancer model and understand their immunomodulatory mechanisms.

Main Methods:

• Design and comparison of nr-mRNA-LPP and sa-mRNA-LPP vaccine formulations.
• Assessment of antitumour immune responses in the TC-1 murine model.
• Analysis of immune cell infiltration, macrophage repolarization, and immune activation in tumors and lymphoid organs.

Main Results:

• Both mRNA-LPP vaccines activated systemic antitumour immunity, increasing CD8+ T cell and NK cell infiltration and repolarizing macrophages to M1 phenotype.
• sa-mRNA-LPP demonstrated superior potency, achieving comparable efficacy at one-fifth the dose of nr-mRNA-LPP.
• sa-mRNA-LPP induced predominantly localized immune responses at the tumor site, unlike nr-mRNA-LPP.

Conclusions:

• The lipopolyplex (LPP) platform efficiently delivers mRNA vaccines.
• sa-mRNA-LPP offers a potent, dose-sparing approach for HPV-associated cancers through localized immune remodeling.
• These findings support the clinical translation of LPP-based mRNA vaccines for HPV-driven cancers.