Melanoma-associated fibroblasts decrease tumor cell susceptibility to NK cell-mediated killing through matrix-metalloproteinases secretion

// Linda Ziani 1, 2, 3 , Thouraya Ben Safta-Saadoun 1, 2, 3 , Johanne Gourbeix 1, 2 , Andrea Cavalcanti 4 , Caroline Robert 2, 3, 5, 6 , Gilles Favre 7 , Salem Chouaib 1, 2, 3 , Jerome Thiery 1, 2, 3 1 INSERM, UMR 1186, Villejuif, France 2 Gustave Roussy Cancer Campus, Villejuif, France 3 University Paris Sud, Faculty of Medicine, Le Kremlin Bicetre, France 4 Department of General Surgery, Gustave Roussy Cancer Campus, Villejuif, France 5 INSERM, UMR 981, Villejuif, France 6 Dermatology Service, Department of Medicine, Gustave Roussy Cancer Campus, Villejuif, France 7 INSERM, UMR 1037, Toulouse, France Correspondence to: Jerome Thiery, email: jerome.thiery@gustaveroussy.fr Keywords: cancer-associated fibroblasts, natural killer cells, matrix-metalloproteinases, MICA/B, melanoma Received: October 11, 2016      Accepted: January 16, 2017      Published: February 20, 2017 ABSTRACT 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.