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.

Claudio Tripodo, Giorgia Travaini, Genti Shyti, Marco Calvaruso, Claudio Tripodo, Alessandra Pattarozzi, Paolo Giannoni, Daniela De Totero, Laura Ottaggio, Ivana Pierri, Simona Zupo, Enrico Balleari, Giovanna Cutrona, Manlio Ferrarini, Roberto Benelli, Rodolfo Quarto, Maria Cristina Mingari, Gabriella Pietra

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Abstract

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(TYR705) 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(+) and indoleamine 2,3-dioxygenase(+) 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(+)CD25(high+)/FOXP3(+) 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.
Lingua originaleEnglish
pagine (da-a)1078-1087
Numero di pagine10
RivistaHaematologica
Volume6
Stato di pubblicazionePublished - 2014

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All Science Journal Classification (ASJC) codes

  • Hematology

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Tripodo, C., Travaini, G., Shyti, G., Calvaruso, M., Tripodo, C., Pattarozzi, A., Giannoni, P., De Totero, D., Ottaggio, L., Pierri, I., Zupo, S., Balleari, E., Cutrona, G., Ferrarini, M., Benelli, R., Quarto, R., Mingari, M. C., & Pietra, G. (2014). 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. Haematologica, 6, 1078-1087.