Neo-organoid of marrow mesenchymal stromal cells secreting interleukin-12 for breast cancer therapy.
Bone marrow-derived mesenchymal stromal cells (MSCs), beneficial for regenerative medicine applications due to their wide differentiation capabilities, also hold promise as cellular vehicles for the delivery of therapeutic plasma-soluble gene products due to their ease of handling, expansion, and genetic engineering. We hypothesized that MSCs, gene enhanced to express interleukin-12 (IL-12) and then embedded in a matrix, may act as an anticancer neo-organoid when delivered s.c. in autologous/syngeneic hosts. We performed such experiments in mice and noted that primary murine MSCs retrovirally engineered to secrete murine IL-12 can significantly interfere with growth of 4T1 breast cancer cells in vivo, with a more substantial anticancer action achieved when these cells are embedded in a matrix. Plasma of mice that received the IL-12 MSC-containing neo-organoids showed increased levels of IL-12 and IFN-gamma. Histopathologic analysis revealed less tumor cells in implants of 4T1 cells with IL-12 MSCs, and the presence of necrotic tumor islets and necrotic capillaries, suggesting antiangiogenesis. We also showed that the anticancer effect exerted by the IL-12 MSCs is immune mediated because it is absent in immunodeficient mice, is not due to systemic IL-12 delivery, and also occurs in a B16 melanoma model. This study therefore establishes the feasibility of using gene-enhanced MSCs in a cell-based neo-organoid approach for cancer treatment.
Lady Davis Institute for Medical Research and Division of Hematology/Oncology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Nicoletta
N
Eliopoulos
Moïra
M
Francois
Marie-Noëlle
MN
Boivin
Daniel
D
Martineau
Jacques
J
Galipeau
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D007167:Immunotherapy; D018664:Interleukin-12 / Q000378:metabolism / Q000627:therapeutic use*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D008648:Mesoderm / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018919:Neovascularization, Physiologic; D009940:Organoids; D017154:Stromal Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate
D018664:Interleukin-12