title: Inhibition of TGF-β signaling in combination with TLR7 ligation re-programs a tumoricidal phenotype in tumor-associated macrophages.
abstract: Inadequate immunity that occurs in a tumor environment is in part due to the presence of M2-type tumor-associated macrophages (TAMs). TGF-β has a multi-functional role in tumor development including modulating the biological activity of both the tumor and TAMs. In this study, using an in vitro TAM/tumor cell co-culture system ligation of TLR7, which is expressed on TAMs but not the tumor cells, in the presence of TGF-β receptor I inhibitor re-programmed the phenotype of the TAMs. In part they adopted the phenotype characteristic of M1-type macrophages, namely they had increased tumoricidal activity and elevated expression of iNOS, CD80 and MHC class II, while TGF-β secretion was reduced. The reprogrammed phenotype was accompanied by enhanced NF-κB nuclear translocation. The pro-angiogenesis factor VEGF was down-regulated and in vivo the number of CD31-positive tumor capillaries was also reduced. Furthermore, in vivo we observed that TLR7 ligation/TGF-β receptor I inhibition increased tumor apoptosis and elevated the number of CD4+, CD8+, and CD19+ cells as well as neutrophils infiltrating the tumor. Our data demonstrate that selective TLR stimulation with TGF-β inhibition can reprogram TAMs towards an M1-like phenotype and thereby provides new perspectives in cancer therapy.
authors: Department of Surgery, LKS Faculty of Medicine, Hong Kong, PR China.
authors: Jiao
authors: J
authors: Peng
authors: Julia Yuen Shan
authors: JY
authors: Tsang
authors: Daxu
authors: D
authors: Li
authors: Na
authors: N
authors: Niu
authors: Derek Hoi Hang
authors: DH
authors: Ho
authors: Kwok Fai
authors: KF
authors: Lau
authors: Vincent Chi Hang
authors: VC
authors: Lui
authors: Jonathan Robert
authors: JR
authors: Lamb
authors: Yan
authors: Y
authors: Chen
authors: Paul Kwong Hang
authors: PK
authors: Tam
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000276:immunology / Q000473:pathology*; D009389:Neovascularization, Pathologic; D016133:Polymerase Chain Reaction; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha