Depletion of M2-like tumor-associated macrophages delays cutaneous T-cell lymphoma development in vivo.
Macrophages have key roles in tumor development and invasion in several human cancers, but little is known about their pathogenic role in cutaneous T-cell lymphoma (CTCL). Herein, we used PCR arrays to profile the expression of inflammatory cytokines in 12 patients with mycosis fungoides (MF), the most common variant of CTCL. Compared with normal controls, MF skin displayed increased mRNA levels of macrophage-related cytokines. Moreover, we detected CD163, a reliable marker of tumor-associated macrophages, in the tumor microenvironment of MF biopsies. To demonstrate that macrophages had a role in CTCL tumorigenesis, we xenografted human CTCL tumor cells in immunocompromised mice and compared tumor development using clodronate-containing liposomes to deplete macrophages in mice. Mice treated with clodronate-containing liposomes show markedly less tumor growth compared with mice treated with phosphate-buffered saline-containing liposomes (P<0.001). We also noted a strong correlation between macrophage depletion and decreased expression of vascular marker, CD31, and lymphatic marker, podoplanin, suggesting a role for macrophages in angiogenesis. In vitro, clodronate-containing liposomes killed activated murine M2 macrophages, but not Hut78 cells, demonstrating selective ability to induce apoptosis in macrophages. Our data indicate that macrophages have a critical role in the progression of Hut78 cell tumor formation in skin, thus providing a new therapeutic strategy for CTCL.
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Xuesong
X
Wu
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Brian C
BC
Schulte
Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada.
Youwen
Y
Zhou
Department of Pediatrics, Section of Rheumatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Dipica
D
Haribhai
Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Alexander C
AC
Mackinnon
Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Jose A
JA
Plaza
Department of Pediatrics, Section of Rheumatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Calvin B
CB
Williams
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. Electronic address: sthwang@mcw.edu.
Sam T
ST
Hwang
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D045744:Cell Line, Tumor; D004002:Clodronic Acid / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry; D016410:Lymphoma, T-Cell, Cutaneous / Q000097:blood* / Q000473:pathology; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009182:Mycosis Fungoides / Q000378:metabolism; D009368:Neoplasm Transplantation; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D012878:Skin Neoplasms / Q000097:blood* / Q000473:pathology; D000098902:CD163 Antigen; D000098853:Podoplanin
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D004002:Clodronic Acid; D016207:Cytokines; D008081:Liposomes; D008562:Membrane Glycoproteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011956:Receptors, Cell Surface; D000098902:CD163 Antigen; C490441:Pdpn protein, mouse; D000098853:Podoplanin