Neuroblastoma Tumor-Associated Mesenchymal Stromal Cells Regulate the Cytolytic Functions of NK Cells

Sabina Di Matteo, Maria Antonietta Avanzini, Gloria Pelizzo, Valeria Calcaterra, Stefania Croce, Grazia Maria Spaggiari, Charles Theuer, Gianvincenzo Zuccotti, Lorenzo Moretta, Andrea Pelosi, Bruno Azzarone

Research output: Contribution to journalArticlepeer-review


Neuroblastoma tumor-associated mesenchymal stromal cells (NB-TA-MSC) have been extensively characterized for their pro-tumorigenic properties, while their immunosuppressive potential, especially against NK cells, has not been thoroughly investigated. Herein, we study the immune-regulatory potential of six primary young and senescent NB-TA-MSC on NK cell function. Young cells display a phenotype (CD105+/CD90+/CD73+/CD29+/CD146+) typical of MSC cells and, in addition, express high levels of immunomodulatory molecules (MHC-I, PDL-1 and PDL-2 and transcriptional-co-activator WWTR1), able to hinder NK cell activity. Notably, four of them express the neuroblastoma marker GD2, the most common target for NB immunotherapy. From a functional point of view, young NB-TA-MSC, contrary to the senescent ones, are resistant to activated NK cell-mediated lysis, but this behavior is overcome using anti-CD105 antibody TRC105 that activates antibody-dependent cell-mediated cytotoxicity. In addition, proliferating NB-TA-MSC, but not the senescent ones, after six days of co-culture, inhibit proliferation, expression of activating receptors and cytolytic activity of freshly isolated NK. Inhibitors of the soluble immunosuppressive factors L-kynurenine and prostaglandin E2 efficiently counteract this latter effect. Our data highlight the presence of phenotypically heterogeneous NB-TA-MSC displaying potent immunoregulatory properties towards NK cells, whose inhibition could be mandatory to improve the antitumor efficacy of targeted immunotherapy.

Original languageEnglish
Article number19
Issue number1
Publication statusPublished - Jan 2023


  • CAF
  • GD2
  • immunosuppression
  • natural killer cells
  • neuroblastoma
  • senescence
  • TAZ
  • tumor microenvironment
  • tumor-associated mesenchymal stromal cells (TA-MSC)
  • WWTR1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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