STING agonist 2'3'-cGAMP as an effective adjuvant for HPV16 peptide vaccine enhances anti-tumor immunity in TC-1 mice...

Adjuvants are critical for enhancing vaccine immunogenicity. The agonists in cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway have demonstrated robust immune activation in preclinical models. Peptide vaccines targeting T cell epitopes of high-risk human papillomavirus (HPV) E6 and E7 represent a promising immunization strategy. To improve immunogenicity, we utilized the STING agonist 2'3'-cGAMP as an adjuvant and evaluated its ability to enhance immune responses and antitumor efficacy.

The immunogenicity and efficacy of a candidate vaccine, consisting of the HPV16 E7_43-77 peptide adjuvanted with 2'3'-cGAMP, were evaluated in established TC-1 tumor transplantation models with different initial tumor sizes (2-3 mm and 5-6 mm in diameter). Tumor-bearing mice received three weekly peritumoral subcutaneous vaccine doses. The effects on tumor suppression, antigen-specific cytotoxic T lymphocyte (CTL) response induction, and related immune mechanisms were investigated both in vitro and in vivo.

Immunization with the E7_43-77 peptide adjuvanted by 2'3'-cGAMP significantly suppressed tumor growth and 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, reduced Myeloid-derived suppressor cells (MDSCs), and increased INF-β levels, as well as promote lymphocyte infiltration and remodeling in tumor immune microenvironment (TME). Mechanistically, 2'3'-cGAMP promoted DC maturation, enhanced T cell proliferation and activation, and strengthened antigen-specific CTL responses by activating the STING-TBK1-IRF3 and STING-NF-κB pathways in peptide-loaded DCs.

The STING agonist 2'3'-cGAMP serves as an effective adjuvant that enhances the therapeutic efficacy of an HPV16 peptide vaccine. These findings indicate its potential as a candidate therapeutic for HPV16 persistent infection and associated malignancies.