STING Agonist 2'3'-cGAMP Enhances HPV16 Peptide Vaccine Efficacy, Suppressing Tumor Growth in TC-1 Mice

Effective adjuvants are crucial for enhancing vaccine immunogenicity, particularly for peptide vaccines targeting cancer. High-risk human papillomavirus (HPV) E6 and E7 peptides are promising targets for immunization strategies against HPV-associated cancers. However, their immunogenicity often requires augmentation. The cGAS-STING signaling pathway is a key innate immune sensor that, when activated, can induce robust immune responses, making its agonists attractive candidates for adjuvants to overcome the limitations of current vaccine platforms.

Researchers evaluated the immunogenicity and efficacy of a candidate vaccine comprising the HPV16 E743-77 peptide adjuvanted with 2'3'-cGAMP in established TC-1 tumor transplantation models. Mice with initial tumor sizes of 2-3 mm and 5-6 mm in diameter received three weekly peritumoral subcutaneous vaccine doses. The study investigated tumor suppression, antigen-specific cytotoxic T lymphocyte (CTL) response induction, and related immune mechanisms using both in vitro and in vivo assays.

Immunization with the E743-77 peptide adjuvanted by 2'3'-cGAMP significantly suppressed tumor growth in TC-1 mice. This combination elicited high levels of Interferon (IFN)-γ and Granzyme B in CD8+ cytotoxic T lymphocytes. The vaccine also enhanced the differentiation of natural killer (NK) cells, dendritic cells (DCs), and M1-type macrophages, while reducing Myeloid-derived suppressor cells (MDSCs). Furthermore, it increased INF-β levels and promoted lymphocyte infiltration and remodeling within the tumor immune microenvironment (TME). Mechanistically, 2'3'-cGAMP promoted DC maturation, enhanced T cell proliferation and activation, and strengthened antigen-specific CTL responses.

This was achieved by activating the STING-TBK1-IRF3 and STING-NF-κB pathways in peptide-loaded DCs.