Engineering a Potent Cancer Vaccine Using Immunoproteasome-Expressing Mesenchymal Stromal Cells

Abstract

Dendritic cells (DCs) excel at cross-presenting antigens, but their effectiveness as cancer vaccine is limited. Here, we describe an innovative vaccine approach using mesenchymal stromal cells (MSCs) engineered to express the immunoproteasome (IPr) complex (MSC-IPr). Such modification instilled efficient antigen cross-presenting abilities associated with enhanced major histocompatibility complex (MHC)I and CD80 expression, de novo expression of interleukin-12 along with higher chemokine secretion. In addition, the cross-presentation capacity of MSC-IPr is highly dependent on AMPK signaling, oxidative phosphorylation and production of reactive oxygen species. Compared to DCs, MSC-IPr hold the ability to cross-present a vastly different epitope repertoire, which translates into potent re-activation of T-cell immunity against EL4 lymphoma and B16 melanoma tumors. Moreover, therapeutic vaccination of animals with pre-established tumors efficiently controls cancer growth, an effect further enhanced when combined with antibodies targeting PD1, CTLA4, LAG3 or 4-1BB under both autologous and allogeneic settings. MSC-IPr constitute therefore a novel subset of non-hematopoietic antigen-presenting cells suitable for the future design of universal cell-based cancer vaccines.

Keywords: Immunoproteasome, Mesenchymal Stromal Cells, Cancer Vaccine, SILACs, Transcriptomics, Metabolomics, Immunopeptidome, Immune-Checkpoint blockers, Universal Vaccine