The CIt protocol: A blueprint to potentiate the immunogenicity of immunoproteasome-reprogrammed mesenchymal stromal cells

Jean-Pierre Bikorimana; Nehme El-Hachem; Jamilah Abusarah; Nicoletta Eliopoulos; Sebastien Talbot; Riam Shammaa; Moutih Rafei

doi:10.1016/j.isci.2022.105537

The CIt protocol: A blueprint to potentiate the immunogenicity of immunoproteasome-reprogrammed mesenchymal stromal cells

iScience. 2022 Nov 9;25(12):105537. doi: 10.1016/j.isci.2022.105537. eCollection 2022 Dec 22.

Authors

Jean-Pierre Bikorimana¹, Nehme El-Hachem^{2

3}, Jamilah Abusarah², Nicoletta Eliopoulos^{4

5}, Sebastien Talbot⁶, Riam Shammaa⁷, Moutih Rafei^{1

2

8}

Affiliations

¹ Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montreal, QC, Canada.
² Department of Pharmacology and Physiology, Université de Montréal, Montreal, QC, Canada.
³ Pediatric Hematology-Oncology Division, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Montreal, QC, Canada.
⁴ Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.
⁵ Department of Surgery, McGill University, Montreal, QC, Canada.
⁶ Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
⁷ IntelliStem Technologies Inc., Toronto, ON, Canada.
⁸ Molecular Biology Program, Université de Montréal, Montreal, QC, Canada.

Abstract

Immunoproteasome-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 the 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 the 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 phagocyte-mediated 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.

Keywords: Cancer; Immune response; Immunology.