Cellular immunity established via immunotherapy holds the potential to eliminate solid tumors. Yet， cancer vaccines have failed to induce tumor-reactive T cells of sufficient quality to control disease. The inducible T cell costimulator (ICOS) pathway has been implicated in both the selective induction of immunity over tolerance as well as licensing of IL-17-polarized cellular immunity. Herein， we evaluated the ability of ICOS ligand (ICOSL) to augment the immunogenicity of adenoviral-based vaccination targeting the unglycosylated MUC1 peptide antigen. Vaccination disrupted immunotolerance in a transgenic mouse model recognizing human MUC1 as a self-antigen， inducing robust MUC1-specific immunity. Augment... More
Cellular immunity established via immunotherapy holds the potential to eliminate solid tumors. Yet， cancer vaccines have failed to induce tumor-reactive T cells of sufficient quality to control disease. The inducible T cell costimulator (ICOS) pathway has been implicated in both the selective induction of immunity over tolerance as well as licensing of IL-17-polarized cellular immunity. Herein， we evaluated the ability of ICOS ligand (ICOSL) to augment the immunogenicity of adenoviral-based vaccination targeting the unglycosylated MUC1 peptide antigen. Vaccination disrupted immunotolerance in a transgenic mouse model recognizing human MUC1 as a self-antigen， inducing robust MUC1-specific immunity. Augmenting vaccination with ICOSL induced a bipolar Th17/Th1 effector profile， marked by increased MUC1-specific IL-17A production and RORγt expression in CD4 but not CD8 T cells which predominantly expressed IFNγ/IL-2 and T-bet. The polarization and maintenance of Th17 cells established following ICOSL augmented vaccination was highly durable， with elevated IL-17A and RORγt levels detected in CD4 T cells up to 10 months after initial immunization. Furthermore， provision of ICOSL significantly enhanced MUC1-specific IgG antibody in response to immunization. ICOSL signaling dramatically influenced CD4 T cell phenotype， altering gene expression of transcription factors and regulators of effector function following immunization. Interestingly， ICOSL augmentation failed to alter the transcriptional profile of CD8 T cells following immunization， affecting the magnitude， but not distribution， of gene expression. Collectively， ICOSL supports the induction of durable， antigen-specific Th17/Th1-mediated immunity in vivo， establishing a vaccination platform to enhance CD4 T cell-mediated antitumor immunity and providing a crucial component of an effective cancer vaccine.
