College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China.
#These authors contributed equally to this work.
Background: The participation of major histocompatibility complex (MHC) in antigen presentation shapes both the breadth and magnitude of specific T cell response. Dendritic cells (DCs) activated with nucleic acid or protein that encodes/incorporates multiple antigenic epitopes elicit MHC class I- and II- biased immunity, respectively. Studies demonstrate that an elevated MHC class I-directed CD8+ cytotoxicity T lymphocyte (CTL) response is able to provide survival benefits to patient with malignant tumor. However, a fully effective cancer therapy must elicit a diverse repertoire of both CD4+ and CD8+ T cell responses, raising demands on a multifaceted activation of the MHC system. Current therapeutic strategies usually lack an orchestrated mobilization of the MHC class I and II responses. Vaccines with little synergistic effect or unmanageable elicitation of the CD4+ and CD8+ T cell immunity usually fail to induce a potent and durable anti-tumor protection.
Methods: Here, cationic nanoemulsions (CNEs) complexed with full-length tumor model antigen ovalbumin (OVA) in the form of mRNA or protein were constructed and used as two antigenic platforms to prepare DCs vaccines with tailored MHC participation (i.e., mRNA-DCs and protein-DCs). In exploring a vaccine regimen with optimal tumor suppressing effect, the mixing ratio of mRNA-DCs and protein-DCs was manipulated.
Results: Therapeutic DCs vaccines involving both antigenic platforms induced better anti-tumor immunity in murine E.G7-OVA lymphoma model and B16-OVA melanoma model, which can be further augmented upon a meticulous reallocation of the MHC class I and II responses.
Conclusion: This work indicated that a simultaneous and coordinated mobilization of the MHC-restricted immunity might potentiate cancer therapy.
Keywords: MHC-restricted immunity, cationic nanoemulsions, mRNA-DCs, protein-DCs, cancer therapy