Marrow stromal cells for interleukin-2 delivery in cancer immunotherapy.
Marrow stromal cells (MSCs) can be easily gene-modified and clonally expanded making them ideal candidates for transgenic cell therapy. However, recent reports suggest that MSCs possess immunosuppressive effects, which may limit their clinical applications. We investigated whether interleukin (IL)-2 gene-modified MSCs can be used to mount an effective immune response against the poorly immunogenic B16 melanoma model. We first show that primary MSCs mixed with B16 cells and injected subcutaneously in syngeneic recipients do not affect tumor growth. On the other hand, IL-2-producing MSCs mixed with B16 cells significantly delayed tumor growth in an IL-2 dose-dependent manner. Furthermore, we observed that matrix-embedded IL-2-producing MSCs injected in the vicinity of preestablished B16 tumors led to absence of tumor growth in 90% of treated mice (p < 0.001). We demonstrated that tumor-bearing mice treated with IL-2-producing MSCs developed CD8-mediated tumor-specific immunity and significantly delayed tumor growth of a B16 cell challenge (p < 0.05). In addition, treatment of cd8-/-, cd4-/- and beige mice revealed that CD8+ and natural killer (NK) cells, but not CD4+ cells, were required to achieve antitumor effect. In conclusion, MSCs can be exploited to deliver IL-2 and generate effective immune responses against melanoma in mice with normal immune systems.
Stagg
John
J
Lady Davis Institute for Medical Research, McGill University, 3755 Côte Ste-Catherine Road, Montreal, Quebec, Canada H3T 1E2.
Lejeune
Laurence
L
Paquin
André
A
Galipeau
Jacques
J
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D001853:Bone Marrow / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015704:CD4 Antigens / Q000235:genetics / Q000502:physiology; D016827:CD8 Antigens / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D007167:Immunotherapy; D007376:Interleukin-2 / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012190:Retroviridae / Q000235:genetics; D012878:Skin Neoplasms / Q000276:immunology / Q000517:prevention & control*; D017154:Stromal Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology
D000970:Antineoplastic Agents; D015704:CD4 Antigens; D016827:CD8 Antigens; D007376:Interleukin-2