Nanoparticle-mediated dual delivery of MHC class I and II antigens enhances T cell immunity and anti-tumor potency.

Abstract

Nanoparticle (NP)-based cancer vaccine therapies conventionally incorporate tumor-associated antigens or neoantigens that are major histocompatibility complex (MHC) class I-restricted, an approach that educates cytotoxic CD8⁺ T cells to respond to tumors. Helper CD4⁺ T cells can support CD8⁺ T cell-mediated responses and are activated by MHC class II-presented peptides. However, strategies to deliver MHC class I and II antigens using NPs as vehicles have not been systematically examined for anti-cancer immunity. In melanoma and colon carcinoma murine models, we evaluated the effects of transporting MHC class I and class II antigens using different NP-based approaches, with the NPs being within the optimal size range for uptake by antigen-presenting dendritic cells. We found that co-delivering MHC class I and II peptides on dual-antigen NPs increased proliferation of cytotoxic and helper T cells relative to single-antigen NPs alone (i.e., either MHC class I or II peptide on a NP) and to mixtures of the single-antigen NPs. For both tumor models, dual-antigen NPs also elicited higher antigen-specific Th1 responses, including up to 8-fold higher interferon (IFN)-γ secretion. Significantly, immunization with the dual-antigen NPs prolonged survival, with 40% of melanoma- and 71% of colon carcinoma-bearing mice surviving, compared to 0% and 13%, respectively, of those treated with component- and dose-equivalent mixtures of single-antigen NPs. This highlights the importance of the antigen delivery strategy and locale with respect to the NP, with the simultaneous co-delivery of both MHC class I and II antigens on the same NP being critical for anti-tumor potency.