Effects of idelalisib, a PI3Kδ inhibitor used in the treatment of Chronic Lymphocytic Leukemia (CLL), on macrophages and its interactions with other therapeutic agents.

ANA COLADO; VALERIA SARAPURA MARTINEZ; HORACIO FERNÁNDEZ GRECCO; GIORDANO MIRTA; MIKELE AMONDARAIN; MARICEF VERGARA RUBIO; ALEXIA VEREERTBRUGGHEN; MORANDE, PABLO E; BORGE MERCEDES; ESTEBAN ELIAS; GREGORIO CORDINI; BEZARES FERNANDO; GAMBERALE ROMINA

San Miguel de Tucumán

Congreso; LXVII Reunion científica anual de la sociedad argentina de inmunología 9-11 de Octubre de 2019. Tucuman; 2019

B-cell receptor associated kinase inhibitors (BCR-Ki) changed the treatment-paradigm in CLL. It was previously reported that ibrutinib, a BCR-Ki for BTK/ITK, impaired M1 polarization and cytokine secretion, and also that entospletinib, a BCR-Ki for SYK, reduced T-cell activation and overcomes leukemic-cell resistance to venetoclax, a Bcl-2 inhibitor recently incorporated in CLL-treatment. Here we evaluated the effect of idelalisib, a BCR-Ki that targets PI3Kδ, on i) macrophage-phenotype and cytokine secretion, and ii) the resistance of leukemic cells to venetoclax induced by activated T-cells.Human monocytes were cultured with GM-CSF+IFN-ɣ or M-CSF+IL-10 to obtain M1 or M2 macrophages respectively. Immobilized anti-CD3 was used to activate T-cells. M1/M2-associated markers, cell-viability and leukemic and T-cell activation were evaluated by flow cytometry, and TNF-α by ELISA. We found that idelalisib did not affect the expression of CD206, CD163 (M2-markers) and CD86 (M1-marker), as reported with other BCR-Ki (n=6), while it impaired TNF-α secretion induced by LPS without affecting macrophage viability (n=8, p