Inhibition of TGF-β signaling in combination with TLR7 ligation re-programs a tumoricidal phenotype in tumor-associated macrophages

Cancer Lett. 2013 May 1;331(2):239-49. doi: 10.1016/j.canlet.2013.01.001. Epub 2013 Jan 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Immunohistochemistry
  • Macrophages / immunology*
  • Male
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms, Experimental / blood supply
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / pathology*
  • Neovascularization, Pathologic
  • Polymerase Chain Reaction
  • Signal Transduction*
  • Toll-Like Receptor 7 / metabolism*
  • Transforming Growth Factor beta / biosynthesis
  • Transforming Growth Factor beta / metabolism*
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Membrane Glycoproteins
  • Tlr7 protein, mouse
  • Toll-Like Receptor 7
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha