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

Oncogene volume 30, pages 2475–2484 (2011)Cite this article

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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.

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Acknowledgements

This research is funded by the NIH/NCI (R01 CA132571-01), and the American Cancer Society (RSG-CSM-116801) grants to VGK, and NIH/NHLBI HL25243 and HL097564 to TJS.

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Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA

    T J Standiford, U Bhan, J Chen, M Newstead & V G Keshamouni

  2. Comprehensive Cancer Center, University of Michigan Medical Center, Ann Arbor, MI, USA

    R Kuick & V G Keshamouni

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  1. T J Standiford
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  2. R Kuick
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Correspondence to V G Keshamouni.

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Standiford, T., Kuick, R., Bhan, U. et al. TGF-β-induced IRAK-M expression in tumor-associated macrophages regulates lung tumor growth. Oncogene 30, 2475–2484 (2011). https://doi.org/10.1038/onc.2010.619

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