Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity.
Although the role of the tumor microenvironment in the process of cancer progression has been extensively investigated, the contribution of different stromal components to tumor growth and/or evasion from immune surveillance is still only partially defined. In this study we analyzed fibroblasts derived from metastatic melanomas and provide evidence for their strong immunosuppressive activity. In coculture experiments, melanoma-derived fibroblasts sharply interfered with NK cell functions including cytotoxicity and cytokine production. Thus, both the IL-2-induced up-regulation of the surface expression of NKp44, NKp30, and DNAM-1 triggering receptors and the acquisition of cytolytic granules were inhibited in NK cells. This resulted in an impairment of the NK cell-mediated killing of melanoma target cells. Transwell cocultures and the use of specific inhibitors suggested that cell-to-cell contact was required for inducing DNAM-1 modulation. In contrast, modulation of NKp44 and NKp30 was due to PGE(2) released by fibroblasts during coculture. Normal skin fibroblasts could also partially affect NK cell phenotype and function. However, the inhibitory effect of tumor-derived fibroblasts was far stronger and directly correlated with their ability to produce PGE(2) either constitutively or upon induction by NK cells.
Balsamo
Mirna
M
Dipartimento di Medicina Sperimentale (DIMES), Università di Genova, and Centro di Eccellenza per la Ricerca Biomedica 16132 Genova, Italy.
Scordamaglia
Francesca
F
Pietra
Gabriella
G
Manzini
Claudia
C
Cantoni
Claudia
C
Boitano
Monica
M
Queirolo
Paola
P
Vermi
William
W
Facchetti
Fabio
F
Moretta
Alessandro
A
Moretta
Lorenzo
L
Mingari
Maria Cristina
MC
Vitale
Massimo
M
D002450:Cell Communication; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D015232:Dinoprostone / Q000378:metabolism; D005347:Fibroblasts / Q000276:immunology* / Q000473:pathology*; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D055629:Natural Cytotoxicity Triggering Receptor 2 / Q000378:metabolism; D054353:Perforin / Q000378:metabolism; D010641:Phenotype; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology
C112837:NCR2 protein, human; D055629:Natural Cytotoxicity Triggering Receptor 2; D054353:Perforin; D053804:Granzymes; D015232:Dinoprostone