Ibrutinib modifies the function of monocyte/macrophage population in chronic lymphocytic leukemia.
In lymphoid organs, nurse-like cells (NLCs) show properties of tumor-associated macrophages, playing a crucial role in chronic lymphocytic leukemia (CLL) cell survival. Ibrutinib, a potent inhibitor of Bruton's tyrosine kinase (BTK), is able to counteract pro-survival signals in CLL cells. Since the effects on CLL cells have been studied in the last years, less is known about the influence of ibrutinib on NLCs properties. We sought to determine how ibrutinib modifies NLCs functions focusing on the balance between immunosuppressive and inflammatory features. Our data show that ibrutinib targets BTK expressed by NLCs modifying their phenotype and function. Treatment with ibrutinib reduces the phagocytic ability and increases the immunosuppressive profile of NLCs exacerbating the expression of M2 markers. Accordingly, ibrutinib hampers LPS-mediated signaling, decreasing STAT1 phosphorylation, while allows IL-4-mediated STAT6 phosphorylation. In addition, NLCs treated with ibrutinib are able to protect CLL cells from drug-induced apoptosis partially through the secretion of IL-10. Results from patient samples obtained prior and after 1 month of treatment with ibrutinib show an accentuation of CD206, CD11b and Tie2 in the monocytic population in the peripheral blood. Our study provides new insights into the immunomodulatory action of ibrutinib on monocyte/macrophage population in CLL.
Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Stefania
S
Fiorcari
Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Rossana
R
Maffei
Department of Medical Sciences, University of Turin and Human Genetics Foundation, Turin, Italy.
Valentina
V
Audrito
Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Silvia
S
Martinelli
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Elisa
E
Ten Hacken
Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Patrizia
P
Zucchini
Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Giulia
G
Grisendi
Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Leonardo
L
Potenza
Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Mario
M
Luppi
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jan A
JA
Burger
Department of Medical Sciences, University of Turin and Human Genetics Foundation, Turin, Italy.
Silvia
S
Deaglio
Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Roberto
R
Marasca
D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D010880:Piperidines; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine
CLL; ibrutinib; immune modulation; microenvironment; nurse-like cells