Abstract B139: Plant viral particle vaccine induces a potent antitumor response through induction of antigen-specific T-cells and overcoming an immunosuppressive tumor microenvironment

Abstract

In order to develop an effective vaccination strategy for cancer, it is necessary to induce robust T-cell responses and to overcome the immunosuppressive tumor microenvironment (TME). To induce anticancer immunity, we focused on a plant viral particle (PVP) that contains-single strand RNA (ssRNA) as a flexible and economical platform to deliver cancer antigens. Initially using PVP loaded with SIINFEKL, we demonstrated the induction of a rapid CD8 T-cell response leading to a significant therapeutic effect in the B16 tumor model. The induction of high levels of CD8 T-cells was also achieved when clinically relevant cancer antigens were used with lysis of human cancer cells expressing these antigens. Further, PVP loaded with whole protein antigen induced CD8 and CD4 T-cell responses against the epitopes delivered through the whole antigen and these cleared established tumors. The mechanisms behind the high immunogenicity of the PVP vaccine revealed that this ssRNA containing vaccine activated the immune mechanisms closely resembling the natural antiviral defence. In a murine model, the immune induction was through the activation of TLR7, leading to release of type I IFN by plasmacytoid dendritic cells and activation of conventional DCs (cDCs) followed with the priming of Th1 immunity. These findings were further supported by experiments using human monocytes derived DCs (moDCs) stimulated in vitro with PVP. The stimulated moDCs released Th1-polarizing cytokines and chemokines, and upregulated CD40 and B7 family surface molecules. Further investigation of the TME demonstrated that cDCs, MHC-II high tumor associated macrophages (TAMs) and tumor-infiltrating neutrophils were recruited into the tumor bed 24 hours after vaccination. While MHC-II low TAMs and myeloid-derived suppressor cells were down-regulated in response to vaccination. This was followed by the increase of tumor-infiltrating lymphocytes (TILs) specific for endogenous tumor antigens. In conclusion, the PVP vaccine is an effective platform to induce T-cells specific to the delivered cancer antigens, and furthermore benefit from its ability to convert an immunosuppressive TME towards an immunostimulatory environment, facilitating the endogenous T-cell epitopes spread. Citation Format: Chuan Wang, Yidao Wang, Alex J. Allen, Jantipa Jobsri, Gareth J. Thomas, Christian H. Ottensmeier, Natalia Savelyeva. Plant viral particle vaccine induces a potent antitumor response through induction of antigen-specific T-cells and overcoming an immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B139.