Tumor-targeted interferon-alpha delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis.
The use of type I interferons (IFNs) in cancer therapy has been limited by ineffective dosing and significant toxicity. Here, we exploited the tumor-homing ability of proangiogenic Tie2-expressing monocytes (TEMs) to deliver IFN-alpha to tumors. By transplanting hematopoietic progenitors transduced with a Tie2 promoter/enhancer-driven Ifna1 gene, we turned TEMs into IFN-alpha cell vehicles that efficiently targeted the IFN response to orthotopic human gliomas and spontaneous mouse mammary carcinomas and obtained significant antitumor responses and near complete abrogation of metastasis. TEM-mediated IFN-alpha delivery inhibited tumor angiogenesis and activated innate and adaptive immune cells but did not impair myelopoiesis and wound healing detectably. These results illustrate the therapeutic potential of gene- and cell-based IFN-alpha delivery and should allow the development of IFN treatments that more effectively treat cancer.
Angiogenesis and Tumor Targeting Research Unit, San Raffaele Institute, 20132 Milano, Italy. depalma.michele@hsr.it
Michele
M
De Palma
Roberta
R
Mazzieri
Letterio S
LS
Politi
Ferdinando
F
Pucci
Erika
E
Zonari
Giovanni
G
Sitia
Stefania
S
Mazzoleni
Davide
D
Moi
Mary Anna
MA
Venneri
Stefano
S
Indraccolo
Andrea
A
Falini
Luca G
LG
Guidotti
Rossella
R
Galli
Luigi
L
Naldini
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism* / Q000637:transplantation; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D011401:Promoter Regions, Genetic; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D014945:Wound Healing
D016898:Interferon-alpha; D011993:Recombinant Fusion Proteins; D042787:Receptor, TIE-2