@article{Paolo Giannoni_Gabriella Pietra_Giorgia Travaini_Rodolfo Quarto_Genti Shyti_Roberto Benelli_Laura Ottaggio_Maria Cristina Mingari_Simona Zupo_Giovanna Cutrona_Ivana Pierri_Enrico Balleari_Alessandra Pattarozzi_Marco Calvaruso_Claudio Tripodo_Manlio Ferrarini_Daniela de Totero_2014, place={Pavia, Italy}, title={Chronic lymphocytic leukemia nurse-like cells express hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages}, volume={99}, url={https://haematologica.org/article/view/7049}, DOI={10.3324/haematol.2013.091405}, abstractNote={Hepatocyte growth factor, produced by stromal and follicular dendritic cells, and present at high concentrations in the sera of patients with chronic lymphocytic leukemia, prolongs the survival of leukemic B cells by interacting with their receptor, c-MET. It is, however, unknown whether hepatocyte growth factor influences microenvironmental cells, such as nurse-like cells, which deliver survival signals to the leukemic clone. We evaluated the expression of c-MET on nurse-like cells and monocytes from patients with chronic lymphocytic leukemia and searched for phenotypic/functional features supposed to be influenced by the hepatocyte growth factor/c-MET interaction. c-MET is expressed at high levels on nurse-like cells and at significantly higher levels than normal on monocytes from patients. Moreover, the hepatocyte growth factor/c-MET interaction activates STAT3<sup>TYR705</sup> phosphorylation in nurse-like cells. Indoleamine 2,3-dioxygenase, an enzyme modulating T-cell proliferation and induced on normal monocytes after hepatocyte growth factor treatment, was detected together with interleukin-10 on nurse-like cells, and on freshly-prepared patients’ monocytes. Immunohistochemical/immunostaining analyses demonstrated the presence of c-MET<sup>+</sup> and indoleamine 2,3-dioxygenase<sup>+</sup> cells in lymph node biopsies, co-expressed with CD68 and vimentin. Furthermore nurse-like cells and chronic lymphocytic monocytes significantly inhibited T-cell proliferation, prevented by anti-transforming growth factor beta and interleukin-10 antibodies and indoleamine 2,3-dioxygenase inhibitors, and supported CD4<sup>+</sup>CD25<sup>high+</sup>/FOXP3<sup>+</sup&gt; T regulatory cell expansion. We suggest that nurse-like cells display features of immunosuppressive type 2 macrophages: higher hepatocyte growth factor levels, produced by leukemic or other microenvironmental surrounding cells, may cooperate to induce M2 polarization. Hepatocyte growth factor may thus have a dual pathophysiological role: directly through enhancement of survival of the leukemic clone and indirectly by favoring T-cell immunosuppression.}, number={6}, journal={Haematologica}, author={Paolo Giannoni and Gabriella Pietra and Giorgia Travaini and Rodolfo Quarto and Genti Shyti and Roberto Benelli and Laura Ottaggio and Maria Cristina Mingari and Simona Zupo and Giovanna Cutrona and Ivana Pierri and Enrico Balleari and Alessandra Pattarozzi and Marco Calvaruso and Claudio Tripodo and Manlio Ferrarini and Daniela de Totero}, year={2014}, month={May}, pages={1078-1087} }