TGF-β-induced IRAK-M Expression in Tumor Associated Macrophages Regulates Lung Tumor Growth

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