Article

The polarization of immune cells in the tumour environment by TGFbeta.

Yale University School of Medicine, 300 Cedar Street, TAC S-569, PO BOX 208011, New Haven, Connecticut 06520, USA.
Nature Reviews Immunology (Impact Factor: 33.84). 08/2010; 10(8):554-67. DOI: 10.1038/nri2808
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ABSTRACT Transforming growth factor-beta (TGFbeta) is an immunosuppressive cytokine produced by tumour cells and immune cells that can polarize many components of the immune system. This Review covers the effects of TGFbeta on natural killer (NK) cells, dendritic cells, macrophages, neutrophils, CD8(+) and CD4(+) effector and regulatory T cells, and NKT cells in animal tumour models and in patients with cancer. Collectively, many recent studies favour the hypothesis that blocking TGFbeta-induced signalling in the tumour microenvironment enhances antitumour immunity and may be beneficial for cancer therapy. An overview of the current drugs and reagents available for inhibiting TGFbeta-induced signalling and their phase in clinical development is also provided.

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    ABSTRACT: Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a cancer of the exocrine pancreas with unmet medical need and is strongly promoted by tumor-associated macrophages (TAMs). The presence of TAMs is associated with poor clinical outcome and their overall role therefore appears to be pro-tumorigenic. The "don't eat me" signal CD47 on cancer cells communicates to the signal regulatory protein-α on macrophages and prevents their phagocytosis. Thus, inhibition of CD47 may offer a new opportunity to turn TAMs against PDAC cells including cancer stem cells (CSCs) as the exclusively tumorigenic population. Experimental Design: We studied in vitro and in vivo the effects of CD47 inhibition on CSCs using a large set of primary pancreatic cancer (stem) cells as well as xenografts of primary human PDAC tissue. Results: CD47 was highly expressed on CSCs, but not on other non-malignant cells in the pancreas. Targeting CD47 efficiently enhanced phagocytosis of a representative set of primary human pancreatic cancer (stem) cells and, even more intriguingly, also directly induced their apoptosis in the absence of macrophages during long-term inhibition of CD47. In patient-derived xenografts models, CD47 targeting alone did not result in relevant slowing of tumor growth, but the addition of Gemcitabine or Abraxane resulted in sustained tumor regression and prevention of disease relapse long after discontinuation of treatment. Conclusions: These data are consistent with efficient in vivo targeting of CSCs and strongly suggest that CD47 inhibition could be a novel adjuvant treatment strategy for PDAC independent of underlying and highly variable driver mutations. Copyright © 2015, American Association for Cancer Research.

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