Tumor-Derived Mesenchymal Stem Cells Use Distinct Mechanisms to Block the Activity of Natural Killer Cell Subsets

Publication date: 19 September 2017
Source:Cell Reports, Volume 20, Issue 12
Author(s): Sabine Galland, Joanna Vuille, Patricia Martin, Igor Letovanec, Anne Caignard, Giulia Fregni, Ivan Stamenkovic
Mesenchymal stem cells (MSCs) display pleiotropic functions, which include secretion of soluble factors with immunosuppressive activity implicated in cancer progression. We compared the immunomodulatory effects on natural killer (NK) cells of paired intratumor (T)- and adjacent non-tumor tissue (N)-derived MSCs from patients with squamous cell lung carcinoma (SCC). We observed that T-MSCs were more strongly immunosuppressive than N-MSCs and affected both NK function and phenotype, as defined by CD56 expression. T-MSCs shifted NK cells toward the CD56^dim phenotype and differentially modulated CD56^bright/dim subset functions. Whereas MSCs affected both degranulation and activating receptor expression in the CD56^dim subset, they primarily inhibited interferon-γ production in the CD56^bright subset. Pharmacological inhibition of prostaglandin E2 (PGE2) synthesis and, in some MSCs, interleukin-6 (IL-6) activity restored NK function, whereas NK cell stimulation by PGE2 alone mimicked T-MSC-mediated immunosuppression. Our observations provide insight into how stromal responses to cancer dampen NK cell activity in human lung SCC.

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Teaser

Galland et al. compare natural killer (NK) cell immunosuppression by mesenchymal stem cells (MSCs) from primary human squamous cell carcinomas and adjacent normal lung tissue. Tumor-associated MSCs exert stronger immunosuppression than normal-tissue-derived MSCs and modulate different NK functions by distinct mechanisms.


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