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

122 Citations (Scopus)

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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Natural Killer Cells
Melanoma
Fibroblasts
Phenotype
Coculture Techniques
Dinoprostone
Immune Evasion
Neoplasms
Tumor Microenvironment
Immunosuppressive Agents
Interleukin-2
Up-Regulation
Cytokines
Skin
Growth

Keywords

  • Activating receptors
  • Cytotoxicity
  • Tumor microenvironment

ASJC Scopus subject areas

  • General

Cite this

Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity. / Balsamo, Mirna; Scordamaglia, Francesca; Pietra, Gabriella; Manzini, Claudia; Cantoni, Claudia; Boitano, Monica; Queirolo, Paola; Vermi, William; Facchetti, Fabio; Moretta, Alessandro; Moretta, Lorenzo; Mingari, Maria Cristina; Vitale, Massimo.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 49, 08.12.2009, p. 20847-20852.

Research output: Contribution to journalArticle

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AU - Balsamo, Mirna

AU - Scordamaglia, Francesca

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AU - Cantoni, Claudia

AU - Boitano, Monica

AU - Queirolo, Paola

AU - Vermi, William

AU - Facchetti, Fabio

AU - Moretta, Alessandro

AU - Moretta, Lorenzo

AU - Mingari, Maria Cristina

AU - Vitale, Massimo

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