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Melanoma-Associated Fibroblasts Modulate NK Cell Phenotype and Antitumor Cytotoxicity

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Melanoma-Associated Fibroblasts Modulate NK Cell Phenotype and Antitumor Cytotoxicity Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity Mirna Balsamoa, Francesca Scordamagliab, Gabriella Pietraa, Claudia Manzinia, Claudia Cantonia,c, Monica Boitanod, Paola Queirolod, William Vermie, Fabio Facchettie, Alessandro Morettaa, Lorenzo Morettaa,c,1, Maria Cristina Mingaria,d, and Massimo Vitaled aDipartimento di Medicina Sperimentale (DIMES), Universita`di Genova, 16132 Genova and Centro di Eccellenza per la Ricerca Biomedica 16132 Genova, Italy; bClinica Malattie dell’Apparato Respiratorio e Allergologia, Dipartimento di Medicina Interna, Universita`di Genova, 16132 Genova, Italy; cIstituto Giannina Gaslini 16147 Genova Italy; dIstituto Nazionale per la Ricerca sul Cancro (IST) 16132 Genova, Italy; and eServizio di Anatomia Patologica, Spedali Civili di Brescia, 25123, Brescia, Italy Edited by Ralph M. Steinman, The Rockefeller University, New York, NY, and approved October 21, 2009 (received for review June 12, 2009) Although the role of the tumor microenvironment in the process of onstrated to interact with NK cells giving rise to different functional cancer progression has been extensively investigated, the contribu- outcomes (19–22). Finally, in pathologic conditions including al- tion of different stromal components to tumor growth and/or eva- lergy, NK-type lymphoproliferative disease of granular lympho- sion from immune surveillance is still only partially defined. In this cytes, non-small cell lung cancer, and AML, NK cells have been study we analyzed fibroblasts derived from metastatic melanomas shown to display unique functional and/or phenotypic alterations and provide evidence for their strong immunosuppressive activity. In (23–26). These findings imply that effective NK cell responses coculture experiments, melanoma-derived fibroblasts sharply inter- established in vitro against transformed cells and/or pathogens may fered with NK cell functions including cytotoxicity and cytokine substantially differ in vivo as a consequence of NK cell interaction production. Thus, both the IL-2-induced up-regulation of the surface with different cell types in different inflammatory or tumor sites. In expression of NKp44, NKp30, and DNAM-1 triggering receptors and this context, it became increasingly evident that tumors can influ- the acquisition of cytolytic granules were inhibited in NK cells. This ence the nature and the efficacy of the immune responses of the resulted in an impairment of the NK cell-mediated killing of mela- host (27). For example, induction of regulatory T cells (Tregs) or noma target cells. Transwell cocultures and the use of specific inhib- myeloid suppressor cells and/or production of several immunosup- itors suggested that cell-to-cell contact was required for inducing pressive factors [including arginase-1, NOS-2, IDO, or TGF-␤]by DNAM-1 modulation. In contrast, modulation of NKp44 and NKp30 tumor cells or components of tumor microenvironment may result was due to PGE2 released by fibroblasts during coculture. Normal skin in functional subversion of tumor-infiltrating immunocompetent fibroblasts could also partially affect NK cell phenotype and function. cells (27). In this context, tumor-associated fibroblasts are a relevant However, the inhibitory effect of tumor-derived fibroblasts was far component of the tumor microenvironment (28). However, very stronger and directly correlated with their ability to produce PGE2 limited information is available on their ability to suppress immune either constitutively or upon induction by NK cells. responses. In this study, we show that fibroblasts derived from IMMUNOLOGY melanomas profoundly affect NK cell functions. Thus, NK cells activating receptors ͉ cytotoxicity ͉ tumor microenvironment reaching the tumor site may be greatly impaired in their anti-tumor activity by the tumor stroma itself. ver the past two decades, major advances have been made in Othe definition of NK cell function including their cytolytic Results activity against virus infected or tumor cells (1–3). The molecular Comparative Analysis of Fibroblasts Derived from Melanomas or mechanisms regulating NK cell functions have been defined thanks Normal Skin. Four primary fibroblast cell lines were established to the discovery of various activating and inhibitory receptors. either from two melanoma metastases (lines TF1 and TF2) or from These receptors primarily include inhibitory receptors specific for skin of two healthy individuals (lines HF1 and HF2). Their surface HLA class I molecules, such as killer-Ig-like receptors (KIRs) and phenotype was analyzed by immunofluorescence and cytofluori- NKG2A and activating receptors, such as NKp30, NKp46, NKp44 metric analysis. As shown in Table 1, all expressed prolyl-4- (collectively termed natural cytotoxicity receptors; NCRs), hydroxylase (P4H; an enzyme involved in the biosynthesis of NKG2D, DNAM-1, NKp80, 2B4, NTBA, CRTAM. The activating collagen), but not the CD106 adhesion molecule (that is expressed receptors recognize various ligands expressed by transformed cells by MSCs) (22, 29) nor the tumor marker GD2 ganglioside. Notably, and/or by certain stressed or activated cells (4–8). Certain activating fibroblasts derived from tumor or normal tissue displayed some receptors including NKp44 and CD69 are induced (9, 10), while phenotypic differences: TF1 and TF2 were CD56-negative and others are up-regulated (NKp30, NKG2D, and, partially, NKp46) expressed high levels of fibroblast activation protein (FAP); while at the NK cell surface by cytokines, such as IL-2, known to HF1 and HF2 were CD56ϩ and expressed lower levels of FAP. The potentiate NK cell activity (11). Upon recognition of specific expression of FAP has been reported as a distinctive feature of ligands, NK-receptors can focalize NK cell responses against po- activated fibroblasts (30). Thus, the phenotypic profile suggests a tentially harmful target cells avoiding reactivity with autologous different activation level on tumor-derived or normal fibroblasts, HLA-class Iϩ normal cells (4). Initially, this information could be achieved by the in vitro analysis of purified peripheral blood NK cell populations and clones expanded in the presence of IL-2 (10, 12). Author contributions: M. Balsamo and M.V. designed research; M. Balsamo, F.S., G.P., C.M., W.V., and F.F. performed research; C.C., M. Boitano, and P.Q. contributed new reagents/ Those studies however, did not explain how NK cell functions could analytic tools; M. Balsamo, M. Boitano, P.Q., A.M., M.C.M., and M.V. analyzed data; and actually be modulated in tissues in vivo. Recently, several studies L.M. and M.V. wrote the paper. attempted to clarify this point. For example, it has been shown that The authors declare no conflict of interest. NK cell function can be modified sharply by several cytokines or This article is a PNAS Direct Submission. ␤ enzymes including IL-15, IL-18, IL-21, IL-23, TGF- , or indoleam- 1To whom correspondence should be addressed. E-mail: lorenzomoretta@ospedale- ine 2,3-dioxigenase (IDO) (11, 13–18). In addition, different cell gaslini.ge.it. types including dendritic cells (DCs), plasmacytoid DC (pDC), This article contains supporting information online at www.pnas.org/cgi/content/full/ monocytes, and mesenchymal stem cells (MSCs) have been dem- 0906481106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0906481106 PNAS ͉ December 8, 2009 ͉ vol. 106 ͉ no. 49 ͉ 20847–20852 Downloaded by guest on September 24, 2021 Table 1. Phenotype of different fibroblast populations Nectin- Fibroblast cell lines FAP P4H MIC A* ULBP1* ULBP2* ULBP3* PVR† 2† CD56 CD106 GD2 HF1 ϩ‡ ϩϪϪϮϪϩϩϩϩϪϪ HF2 ϩϩϪϪϪϪϩϮϩϪϪ TF1 ϩϩϩ ϩ Ϫ Ϫ Ϯ Ϫ ϩϩϩ ϩ Ϫ Ϫ Ϫ TF2 ϩϩ ϩ Ϯ Ϫ Ϯ Ϫ ϩϩ ϩ Ϫ Ϫ Ϫ Data are expressed as negative control m.f.i. (mean fluorescence intensity). Fold Increase, 0 (Ϫ); 1–4 (Ϯ ); 4–9 (ϩ); 9–16 (ϩϩ); Ͼ16 (ϩϩϩ). *, NKG2D ligands. †, DNAM-1 ligands. respectively. Regarding the known ligands for activating NK re- of IL-2, NK cells were partially triggered by mAb specific for NKp44 ceptors, both tumor and normal fibroblasts expressed the DNAM-1 (a receptor expressed upon NK cell activation), while responses receptor ligands PVR and Nectin-2, whereas NKG2D ligands were induced by anti-NKp46 and anti-NKp30 mAbs were substantially not expressed at significant levels (4). increased. At day 6, the increment of cytotoxicity was more evident and involved also NKG2D and DNAM-1 receptors. Addition of Tumor-Derived Fibroblasts Inhibit NK Cell Function. To investigate a tumor-derived fibroblasts at the onset of the cultures resulted in possible effect of tumor-derived fibroblasts on NK cells, mixed cell partial inhibition of these functional changes. Although this effect cultures were set up. NK cells, freshly isolated from unrelated was detectable at day 2 of coculture, it became more evident at day healthy donors were cocultured with different fibroblast cell lines 6. In particular, in the presence of TF1 and TF2 the triggering for 2 or 6 days. The function of the major NK cell triggering capability of NKp44 and DNAM-1 was impaired. The NKp30 and receptors (including NKp46, NKp30, NKp44, NKG2D, and NKG2D activation pathways were partially affected, while the DNAM-1) was then analyzed by the use of specific mAbs in a ϩ NKp46 pathway was only marginally inhibited. At variance with redirected killing assay against the Fc␥R P815 target cell line. At tumor-derived fibroblasts, normal fibroblasts (lines HF1 and HF2) day 2 (Fig. 1A, Left) and day 6 (Table S1) neither normal (HF1, only minimally modified NK cell
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