Novel strategy to enhance antigen presentation and CD8 T cell immunity for curative efficacy of intranasal therapeutic HPV peptide vaccination in preclinical vaginal HPV tumor model

Abstract

Abstract Immune checkpoint modulation to enhance antitumor immunity while minimizing immune suppressive responses within tumors has proven to be a highly successful cancer treatment strategy, but, often with toxic side effects and financial constraints. Using preclinical models of human papillomavirus (HPV) cancers, we tested vaccination employing adjuvants with diverse modes of action to promote antigen presentation and T cell immunity. We employed the combination of α-galactosylceramide (α-GalCer), a potent inducer of NKT cells and CpG-containing oligo-deoxynucleotide (CpG-ODN) that function through the TLR9 pathway. Since most HPV tumors occur at mucosal tissues, we used the mucosal intranasal route for vaccination with E6 and E7 peptides representing tumor-specific antigens to treat vaginal HPV+ TC-1 tumors in mice. Previously, we observed that vaccination using α-GalCer adjuvant alone reduced tumor growth but, complete and durable tumor regression required supplementing the vaccine with anti-4-1BB checkpoint modulating antibody that has clinical safety concerns. We now observed that intranasal HPV peptide vaccine incorporating α-GalCer and CpG-ODN adjuvants, rendered tumor-free survival advantage. Correlates of tumor protection included doubling the number of CD8 T cells exhibiting enhanced cytotoxic potential within the tumor and 84% increase in the ratio of CD8 T cells to regulatory T cells relative to vaccination with either adjuvant alone. Intranasal vaccination delivering α-GalCer plus CpG-ODN allows for the activation of dendritic cells through both classical and alternative licensing pathways and permits the secretion of a diverse set of chemokines to attract enhanced populations of naïve CD8+ T cells.