Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity

Mirna Balsamo, Francesca Scordamaglia, Gabriella Pietra, Claudia Manzini, Claudia Cantoni, Monica Boitano, Paola Queirolo, William Vermi, Fabio Facchetti, Alessandro Moretta, Lorenzo Moretta, Maria Cristina Mingari, Massimo Vitale

Research output: Contribution to journalArticle

Abstract

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 PGE2 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 PGE2 either constitutively or upon induction by NK cells.

Original languageEnglish
Pages (from-to)20847-20852
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number49
DOIs
Publication statusPublished - Dec 8 2009

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Keywords

  • Activating receptors
  • Cytotoxicity
  • Tumor microenvironment

ASJC Scopus subject areas

  • General

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