TGF-β-induced IRAK-M expression in tumor-associated macrophages regulates lung tumor growth
Open Access
- 31 January 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 30 (21), 2475-2484
- https://doi.org/10.1038/onc.2010.619
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 tumor growth factor-β (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 (IL) receptor-associated kinase (IRAK)-M is an inactive serine/threonine kinase, predominantly expressed in macrophages and is a potent negative regulator of TLR signaling. In this study, we show that TAMs express significantly higher levels of IRAK-M compared with peritoneal macrophages in a syngeneic mouse model of lung cancer. Subcutaneous implantation of Lewis lung carcinoma cells in IRAK-M−/− mice resulted in a five-fold reduction in tumor growth as compared with tumors in wild-type (WT) animals. Furthermore, compared with 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, interferon-γ (IFN-γ) and inducible nitric oxide synthase. Human lung cancer cells induced IRAK-M expression in human peripheral blood mononuclear cells (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.Keywords
This publication has 47 references indexed in Scilit:
- SMAD4 Is Required for Development of Maximal Endotoxin TolerancePublished by The American Association of Immunologists ,2010
- TGF-² Signaling Pathway in Lung Adenocarcinoma InvasionJournal of Thoracic Oncology, 2010
- Gene expression–based survival prediction in lung adenocarcinoma: a multi-site, blinded validation studyNature Medicine, 2008
- Loss of the innate immunity negative regulator IRAK-M leads to enhanced host immune defense against tumor growthMolecular Immunology, 2007
- Sepsis-induced suppression of lung innate immunity is mediated by IRAK-MJCI Insight, 2006
- Toll-like receptor signallingNature Reviews Immunology, 2004
- Tumour-educated macrophages promote tumour progression and metastasisNature Reviews Cancer, 2004
- Alternative activation of macrophagesNature Reviews Immunology, 2003
- Identification and characterization of murine IRAK-MBiochemical and Biophysical Research Communications, 2002
- The role of tumour‐associated macrophages in tumour progression: implications for new anticancer therapiesThe Journal of Pathology, 2002