A sugar modified amphiphilic cationic nano-adjuvant ceased tumor immune suppression and rejuvenated peptide vaccine induced antitumor immunity in cervical cancer

Abstract

Human papilloma virus (HPV), one of the most common cancer-causing viruses, accounts for more than 90% of human anal and cervical cancers. Clinical studies have focused on adjuvant therapy with vaccines to improve therapeutic outcomes in patients with late-stage HPV-related cancers. In the present study, a mannose receptor (CD206) targeting a lithocholic acid-modified polyethylenimine (PEI) nano-adjuvant delivering the toll-like receptor 7/8 agonist, resiquimod (R848) (mLAPMi-R848), in a HPV E6- and E7-expressing TC-1 tumor murine model was developed. Peritumoral administration of mLAPMi resulted in enhanced accumulation in tumor/tumor-draining lymph nodes and significantly targeted antigen presenting cells like macrophage and dendritic cells. PEI-based nanocarriers can exploit the adjuvant potency of R848 and improve the antitumor immunity. Hence, co-administration of mLAPMi-R848 along with an E6E7 peptide in TC-1 tumor mice eradicated tumor burden and elicited splenocyte-induced cytotoxicity in TC-1 cancer cells. In a bilateral TC-1 tumor model, administration of mLAPMi-R848 and E6E7 peptide significantly suppressed both primary and secondary tumor burdens and improved the overall survival rate. Immune cell profiling revealed elevated levels of mature DCs and CD8+ T cells but reduced levels of tumor-associated immunosuppressive cells (TAICs) like myeloid derived suppressor cells (MDSCs) and regulatory T (Treg) cells in distal tumors. Overall, this study demonstrated that mLAPMi-R848 has improved the antitumor immunity of the peptide antigen against HPV-induced cancers by targeted immunodulation of antigen presenting cells (APCs) and reducing TAICs. Furthermore, this nano-adjuvant has the potential to offer a new treatment option for patients with cervical cancer and can be applied for the treatment of other HPV induced cancers.