Melanoma-associated fibroblasts decrease tumor cell susceptibility to NK cell-mediated killing through matrix-metalloproteinases secretion
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Linda Ziani1,2,3, Thouraya Ben Safta-Saadoun1,2,3, Johanne Gourbeix1,2, Andrea Cavalcanti4, Caroline Robert2,3,5,6, Gilles Favre7, Salem Chouaib1,2,3, Jerome Thiery1,2,3
1INSERM, UMR 1186, Villejuif, France
2Gustave Roussy Cancer Campus, Villejuif, France
3University Paris Sud, Faculty of Medicine, Le Kremlin Bicêtre, France
4Department of General Surgery, Gustave Roussy Cancer Campus, Villejuif, France
5INSERM, UMR 981, Villejuif, France
6Dermatology Service, Department of Medicine, Gustave Roussy Cancer Campus, Villejuif, France
7INSERM, UMR 1037, Toulouse, France
Jerome Thiery, email: [email protected]
Keywords: cancer-associated fibroblasts, natural killer cells, matrix-metalloproteinases, MICA/B, melanoma
Received: October 11, 2016 Accepted: January 16, 2017 Published: February 20, 2017
Cancer-associated fibroblasts (CAFs) play a central role in the complex process of tumor-stroma interaction and promote tumor growth. Emerging evidences also suggest that these fibroblasts are involved in the alteration of the anti-tumor immune response by impacting several immune cell populations, especially through their secretion of pro-inflammatory and immunosuppressive factors in the tumor microenvironment. However, the underlying immuno-modulating mechanisms triggered by these fibroblasts are still only partially defined. In this study, we provide evidence that melanoma-associated fibroblasts decrease the susceptibility of melanoma tumor cells to NK-mediated lysis through the secretion of active matrix metalloproteinases. This secretion reduces the expression of the two NKG2D ligands, MICA/B, at the surface of tumor cells and consequently decreases the NKG2D-dependent cytotoxic activity of NK cells against melanoma tumor cells. Together, our data demonstrate that the modification of tumor cell susceptibility to killer cells is an important determinant of the anti-tumor immune response alteration triggered by CAFs.
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