The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2017-04, Vol.66 (4), p.461-473
• Main Authors: Colado, Ana, Almejún, María Belén, Podaza, Enrique, Risnik, Denise, Stanganelli, Carmen, Elías, Esteban Enrique, Dos Santos, Patricia, Slavutsky, Irma, Fernández Grecco, Horacio, Cabrejo, María, Bezares, Raimundo Fernando, Giordano, Mirta, Gamberale, Romina, Borge, Mercedes
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Apoptosis; Cancer Research; Cell Proliferation - drug effects; Cells; Cells, Cultured; Clinical trials; Female; Humans; Immunology; Indazoles - pharmacology; Kinases; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Lymphocyte Activation - drug effects; Lymphocytes; Macrophages - immunology; Male; Medicine; Medicine & Public Health; Middle Aged; Oncology; Original; Original Article; Oxazines - pharmacology; Phagocytosis - drug effects; Phosphorylation - drug effects; Proteins; Pyrazines - pharmacology; Pyridines - pharmacology; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Rituximab - pharmacology; Syk Kinase - antagonists & inhibitors; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; ZAP-70 Protein-Tyrosine Kinase - metabolism
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-016-1946-y

Small molecules targeting kinases involved in B cell receptor signaling are showing encouraging clinical activity in chronic lymphocytic leukemia (CLL) patients. Fostamatinib (R406) and entospletinib (GS-9973) are ATP-competitive inhibitors designed to target spleen tyrosine kinase (Syk) that have shown clinical activity with acceptable toxicity in trials with CLL patients. Preclinical studies with these inhibitors in CLL have focused on their effect in patient-derived leukemic B cells. In this work we show that clinically relevant doses of R406 and GS-9973 impaired the activation and proliferation of T cells from CLL patients. This effect could not be ascribed to Syk-inhibition given that we show that T cells from CLL patients do not express Syk protein. Interestingly, ζ-chain-associated protein kinase (ZAP)-70 phosphorylation was diminished by both inhibitors upon TCR stimulation on T cells. In addition, we found that both agents reduced macrophage-mediated phagocytosis of rituximab-coated CLL cells. Overall, these results suggest that in CLL patients treated with R406 or GS-9973 T cell functions, as well as macrophage-mediated anti-tumor activity of rituximab, might be impaired. The potential consequences for CLL-treated patients are discussed.