Inhibition of TGF-B 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-beta 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-beta 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-beta secretion was reduced. The reprogrammed phenotype was accompanied by enhanced NF-kappaB 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-beta 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-beta inhibition can reprogram TAMs towards an M1-like phenotype and thereby provides new perspectives in cancer therapy.