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.
Highlights
Over the past decade, the tumor microenvironment has gained much attention as a critical determinant of tumor progression and clinical outcome [1,2,3]
In order to study the role of melanoma-associated fibroblasts on the modulation of melanoma tumor cell susceptibility to natural killer (NK) cell-mediated lysis, we established four Cancer-Associated Fibroblast (CAF) and three normal skin fibroblasts (NF) primary cell populations from melanoma patient’s tumor resection and from normal skin (Table 1)
The concentration of both soluble MICA (sMICA) and sMICB were significantly increased in the supernatant of T1 melanoma tumor cells after treatment with the CAF14 conditioned medium (CM) compared to control cells (Figure 3D). These results suggest that melanoma-associated fibroblasts protect melanoma tumor cells against NK-mediated cytotoxicity by the secretion of soluble factors leading to a decrease of MICA/B expression at the surface of tumor cells, most likely by a mechanism which involved MICA and MICB shedding at the melanoma tumor cell surface
Summary
The tumor microenvironment has gained much attention as a critical determinant of tumor progression and clinical outcome [1,2,3]. During the past few years, it has been either directly demonstrated or suggested that these activated tumor-associated fibroblasts can affect both the innate and the adaptive antitumor immune response, especially by the secretion of pro-inflammatory and immunosuppressive factors in the tumor microenvironment [19, 20] In this regard, the secretion of TGF-β by CAFs potentially affects several immune cell populations [21], including dendritic cells (by inhibiting their migration, maturation and antigen presentation capabilities [22]), regulatory T cells (Tregs) (by increasing their number within the tumor microenvironment through the induction of FOXP3 expression [23]), cytotoxic T lymphocytes (CTL) (by interfering with their function and frequency within the tumor [24, 25]) and natural killer (NK) cells (by attenuating their interferon-γ (IFN-γ) production and their expression of NK-activating receptors including NKG2D, NKp30 and NKp44 [26,27,28]). Studies involving melanoma, hepatocellular and colorectal carcinoma-derived fibroblasts have shown that CAFs can decrease the expression of several NK activating receptors (including NKp30, NKp44 and NKG2D) on the NK cell surface through the secretion of prostaglandin E2 (PGE2) and/or indoleamine-2,3dioxygenase (IDO) [34,35,36] leading to an attenuate cytotoxic activity of NK cells against their tumor target cells
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