Elevating MHC I expression on tumor cells by nanovesicles loading tyrosine kinase inhibitors can improve the efficacy of cancer vaccines

Introduction: Cancer vaccines work through activating tumor-specific T cells, which can specifically attack cancer cells by recognizing antigens binding with Major-Histocompatibility-Complex I (MHC I) molecules. The downregulation or loss of MHC I expression on tumor cells can affect the efficacy of cancer vaccines.Methods: Herein, to increase the MHC I expression on tumor cells, a nanovesicle-based strategy was developed to improve the efficacy of  cancer vaccines. Several clinically applied medicines, such as tyrosine kinase inhibitors (TKIs), were screened for their capacity to upregulate MHC I.Results: Two TKIs, Sunitinib and Sorafenib, were found to be very effective in elevating MHC I expression, and they were encapsulated into redox-responsive nanovesicles respectively (SUN-KD10 or SOR-KD10), which demonstrated favourable tumor-targeting capabilities in the tumor microenvironment. Sunitinib or Sorafenib activates the IFNγ/STAT1 pathway, which improve the expression of MHC I. When combined with whole-tumor-antigen-loaded nanovaccines, these nanovesicle formulations elicited a synergistic antitumor effect in both breast cancer and melanoma mouse models. The tumors in the tumor-bearing mice treated with combined strategy grew more slowly and the survival times of such mice are significantly prolonged.Discussion: The studies demonstrated that more tumor-specific T cells were activated in the combined strategy treated mice, suggesting improved immune-mediated tumor clearance. This combinatorial approach provides a promising strategy to overcome immune evasion and to enhance the therapeutic outcomes of cancer vaccine-based immunotherapy by using clinical-applied medicines with cancer vaccines.