Engineering immunoproteasome-expressing mesenchymal stromal cells: A potent cellular vaccine for lymphoma and melanoma in mice

Abstract

Summary Dendritic cells (DCs) excel at cross-presenting antigens, but their effectiveness as cancer vaccine is limited. Here, we describe a vaccination approach using mesenchymal stromal cells (MSCs) engineered to express the immunoproteasome complex (MSC-IPr). Such modification instills efficient antigen cross-presentation abilities associated with enhanced major histocompatibility complex class I and CD80 expression, de novo production of interleukin-12, and higher chemokine secretion. This cross-presentation capacity of MSC-IPr is highly dependent on their metabolic activity. Compared with 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 and A20 lymphomas and B16 melanoma tumors. Moreover, therapeutic vaccination of mice with pre-established tumors efficiently controls cancer growth, an effect further enhanced when combined with antibodies targeting PD-1, CTLA4, LAG3, or 4-1BB under both autologous and allogeneic settings. Therefore, MSC-IPr constitute a promising subset of non-hematopoietic antigen-presenting cells suitable for designing universal cell-based cancer vaccines.

Humoral Immunity to Allogeneic Immunoproteasome-Expressing Mesenchymal Stromal Cells Requires Efferocytosis by Endogenous Phagocytes

“…To generate the MSC-IPr from BM-derived MSCs, a retroviral construct designed to deliver the main three subunits of the immunoproteasome (IPr) was used to transduce MSCs, as previously described in detail elsewhere [ 19 ]. The transduction efficiency was confirmed by assessing eGFP expression using flow cytometry and immunoblotting of the IPr subunits.…”

“…The collection, isolation and sequencing of cellular RNA were performed as previously described [ 19 ]. Raw RNA-seq read count data were summarized at the gene level with Htseq-count (version 0.10 add ref) from reads aligned to the mouse genome (GRCm39).…”

“…Raw RNA-seq read count data were summarized at the gene level with Htseq-count (version 0.10 add ref) from reads aligned to the mouse genome (GRCm39). Differentially expressed genes between MSC-IPr and Ctl MSCs were calculated by DESeq2 (v.1.26) [ 19 ]. Pre-ranked gene set enrichment (GSEA) was performed on the list of differentially expressed genes according to their log2 fold change.…”

“…An elegant study by Abusarah et al recently reported a newly engineered cell vaccine designed to overcome most of the hurdles seen with the use of DCs in cancer vaccination [ 19 ]. By de novo expression of the immunoproteasome (IPr) complex in mesenchymal stromal cells (MSCs), potent activation of the immune system was achieved [ 19 ].…”

“…An elegant study by Abusarah et al recently reported a newly engineered cell vaccine designed to overcome most of the hurdles seen with the use of DCs in cancer vaccination [ 19 ]. By de novo expression of the immunoproteasome (IPr) complex in mesenchymal stromal cells (MSCs), potent activation of the immune system was achieved [ 19 ]. More specifically, the use of a both syngeneic and allogeneic MSC-IPr vaccine pulsed with tumor cell lysate cured pre-established T-/B-cell lymphomas as well as B16F0 melanoma.…”