Tumor-Derived Mesenchymal Stem Cells Use Distinct Mechanisms to Block the Activity of Natural Killer Cell Subsets
Sabine Galland,
Joanna Vuille,
Patricia Martin,
Igor Letovanec,
Anne Caignard,
Giulia Fregni,
Ivan Stamenkovic
Affiliations
Sabine Galland
Experimental Pathology Service, Institute of Pathology, CHUV, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 25, 1011 Lausanne, Switzerland
Joanna Vuille
Experimental Pathology Service, Institute of Pathology, CHUV, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 25, 1011 Lausanne, Switzerland
Patricia Martin
Experimental Pathology Service, Institute of Pathology, CHUV, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 25, 1011 Lausanne, Switzerland
Igor Letovanec
Experimental Pathology Service, Institute of Pathology, CHUV, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 25, 1011 Lausanne, Switzerland
Anne Caignard
INSERM 1160, Institut Universitaire d’Hématologie, Hôpital Saint Louis, 1, Avenue Claude Vellefaux, 75010 Paris, France
Giulia Fregni
Experimental Pathology Service, Institute of Pathology, CHUV, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 25, 1011 Lausanne, Switzerland
Ivan Stamenkovic
Experimental Pathology Service, Institute of Pathology, CHUV, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 25, 1011 Lausanne, Switzerland
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 CD56dim phenotype and differentially modulated CD56bright/dim subset functions. Whereas MSCs affected both degranulation and activating receptor expression in the CD56dim subset, they primarily inhibited interferon-γ production in the CD56bright 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.
