The CIt Protocol: A Blueprint to Potentiate the Immunogenicity of Immunoproteasome-Reprogrammed Mesenchymal Stromal Cells

Abstract

SUMMARYImmunoproteasome-reprogrammed mesenchymal stromal cells (IRMs) can surpass dendritic cells at eliciting tumor-specific immunity. However, the current IRM vaccination regimen remains clinically unsuitable due to the relatively high dose of IRMs needed. Since administration of a lower IRM dose triggers a feeble anti-tumoral response, we aimed to combine this vaccination regimen with different modalities to fine-tune the potency of the vaccine. In a nutshell, we found that co-administration of IRMs and interleukin-12 accentuates the anti-tumoral response, whereas the cross-presentation potency of IRMs is enhanced via intracellular succinate build-up, delayed endosomal maturation, and increased endosome-to-cytosol plasticity. Stimulating phagocytemediated cancer efferocytosis by blocking the CD47-SIRPα axis was also found to enhance IRM vaccine outcomes. Upon designing a single protocol combining the abovementioned strategies, 60% of treated animals exhibited a complete response. Altogether, this is the first IRM-based vaccination study, optimized to simultaneously target three vaccine-related pitfalls: T-cell response, antigen cross-presentation, and cancer phagocytosis.

Funding Information: This work was supported by an operating grant from the Cancer Research Society (#OG834469), an innovation to impact grant from the Canadian Cancer Society (#706201), and a Discovery grant from the National Research and Engineering Council of Canada (#RGPIN/06101-2014).

Declaration of Interests: The authors declare no competing financial interests.

Ethics Approval Statement: All animal protocols were approved by the Animal Care Committee (CDEA) of Université de Montréal.