Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid-derived suppressor cell expansion and macrophage infiltration in tumor stroma.
BALB-neuT mice expressing an activated rat c-erbB-2/neu transgene under the mouse mammary tumor virus long terminal repeat show enhanced hematopoiesis with hyperproduction of myeloid-derived suppressor cells (MDSC) because of vascular endothelial growth factor (VEGF) secreted by the tumor. Here, we show that both tumor and stromal cells express matrix metalloproteinase-9 (MMP-9), thereby increasing the levels of pro-MMP-9 in the sera of tumor-bearing mice. Treatment with amino-biphosphonates impaired tumor growth, significantly decreased MMP-9 expression and the number of macrophages in tumor stroma, and reduced MDSC expansion both in bone marrow and peripheral blood by dropping serum pro-MMP-9 and VEGF. We dissected the role of tumor-derived MMP-9 from that secreted by stromal leukocytes by transplanting bone marrow from MMP-9 knockout mice into BALB-neuT mice. Although bone marrow progenitor-derived MMP-9 had a major role in driving MDSC expansion, amino-biphosphonate treatment of bone marrow chimeras further reduced both myelopoiesis and the supportive tumor stroma, thus enhancing tumor necrosis. Moreover, by reducing MDSC, amino-biphosphonates overcome the tumor-induced immune suppression and improved the generation and maintenance of antitumor immune response induced by immunization against the p185/HER-2. Our data reveal that suppression of MMP-9 activity breaks the vicious loop linking tumor growth and myeloid cell expansion, thus reducing immunosuppression. Amino-biphosphonates disclose a specific MMP-9 inhibitory activity that may broaden their application above their current usage.
Immunotherapy and Gene Therapy Unit, Department of Experimental Oncology, Fondazione Istituto Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori, Milan, Italy. cecilia.melani@istitutotumori.mi.it
Cecilia
C
Melani
Sabina
S
Sangaletti
Francesca M
FM
Barazzetta
Zena
Z
Werb
Mario P
MP
Colombo
D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology* / Q000473:pathology; D016026:Bone Marrow Transplantation; D003114:Colony-Forming Units Assay; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D006410:Hematopoiesis; D007093:Imidazoles; D007108:Immune Tolerance; D007167:Immunotherapy; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A; D000077211:Zoledronic Acid
D004164:Diphosphonates; D007093:Imidazoles; D020780:Matrix Metalloproteinase 9; D018719:Erb-b2 Receptor Tyrosine Kinases; D042461:Vascular Endothelial Growth Factor A; D000077211:Zoledronic Acid