Inhibition of TGF-β signaling in combination with TLR7 ligation re-programs a tumoricidal phenotype in tumor-associated macrophages
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AbstractInadequate 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. © 2013 Elsevier Ireland Ltd.
All Author(s) ListPeng J., Tsang J.Y.S., Li D., Niu N., Ho D.H.H., Lau K.F., Lui V.C.H., Lamb J.R., Chen Y., Tam P.K.H.
Journal nameCancer Letters
Year2013
Month5
Day1
Volume Number331
Issue Number2
PublisherElsevier BV
Place of PublicationNetherlands
Pages239 - 249
ISSN0304-3835
eISSN1872-7980
LanguagesEnglish-United Kingdom
KeywordsFunctional re-programming, TGF-β, TLR4, TLR7, Tumor-associated macrophages

Last updated on 2020-12-07 at 01:16