TGF-β-induced IRAK-M expression in tumor-associated macrophages regulates lung tumor growth

Abstract

Tumor associated macrophages (TAMs) constitute a major component of the immune cell infiltrate observed in the tumor microenvironment (TME). Factors present in the TME including TGF-β, allow tumors to circumvent host mediated immune responses to promote tumor progression. However, the molecular mechanism(s) involved are not clear. Toll-like receptors (TLRs) are important mediators of innate immune responses by immune cells, whose activation triggers the production of molecules required for anti-tumoral responses. Interleukin receptor associated kinase (IRAK)-M is an inactive serine/threonine kinase, predominantly expressed in macrophages and is a potent negative regulator of TLR signaling. Here we show that TAMs express significantly higher levels of IRAK-M compared to peritoneal macrophages (PEMs) in a syngeneic mouse model of lung cancer. Subcutaneous implantation of LLC cells in IRAK-M−/− mice resulted in a five-fold reduction in tumor growth, as compared to tumors in wild type animals. Furthermore, compared to WT TAMs, TAMs isolated from IRAK-M−/− mice displayed features of a classically activated (M1) rather than alternatively activated (M2) phenotype, as manifest by greater expression of IL-12, IFN-γ, and iNOS. Human lung cancer cells induced IRAK-M expression in human PBMCs when co-cultured together. Tumor cell-induced expression of IRAK-M was dependent on the activation of TGF-β pathway. Similarly, treatment of human PBMCs or mouse macrophage cell line, RAW 264.4, with TGF-β, induced IRAK-M expression. Interestingly, IRAK-M gene expression in 439 human lung adenocarcinoma tumors correlated with poor survival in patients with lung cancer. Together, our data demonstrates that TGF-β-dependent induction of IRAK-M expression is an important, clinically relevant mechanism by which tumors may circumvent anti-tumor responses of macrophages.

HMGB1 was a pivotal synergistic effecor for CpG oligonucleotide to enhance the progression of human lung cancer cells

“…[26][27][28] Accumulating data suggested that TLRs were involved in the development of lung cancer. 29,30 Protein levels of TLR4 and TLR9 were strongly expressed in lung cancer tissues. 31 The expression of TLR4 was correlated with the malignancy of lung cancer.…”

Crosstalk of mesenchymal stem cells and macrophages promotes cardiac muscle repair

“…These data also suggest that besides recruiting macrophages, MSCs themselves are also necessary for the functional cardiac repair. Since previous studies have highlighted an important counteraction between TGF␤1 and BMP7 in the epithelial-to-mesenchymal transition for fibrosis (Buijs et al, 2007;Khan et al, 2011;Liu et al, 2014;Shen et al, 2014;Wang and Hirschberg, 2003), and macrophages express high TGF␤1 (Ding et al, 1993;Lazdins et al, 1991;Standiford et al, 2011;Vignola et al, 1996;Xiao Fig. 7.…”

“…Since TGF␤1 has been reported to be highly expressed by macrophages (Ding et al, 1993;Lazdins et al, 1991;Standiford et al, 2011;Vignola et al, 1996;Xiao et al, 2014), we thus examined the expression of TGF␤1 and BMP7 in the isolated macrophages and MSCs from the recipient heart (Fig. 7A).…”

Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment

“…22,23 Because we have demonstrated that AML blasts do not spontaneously release IL-10, IL-4, GM-CSF, and TGF-b into culture supernatants, we investigated whether the increased arginase II secretion could have a role in CD206 upregulation on healthy donor monocytes. We cocultured monocytes from healthy patients with supernatants from AML blasts with or without NOHA and L-NMMA and demonstrated that the inhibitors significantly reduced the expression of CD206 on monocytes from 70% to 22.5% ( Figure 3B).…”