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

AMONDARAIN, MIKELE; GAMBERALE ROMINA; BORGE MERCEDES

Tucumán

Congreso; LXVII Congreso Sociedad Argentina de Inmunología,; 2019

B-cell receptor signaling inhibitors (BCRi) have changed the treatment-paradigmin CLL. Some BCRi were successfully used to overcome leukemic-cell resistanceto venetoclax, a Bcl-2 inhibitor recently incorporated in CLL-treatment. On theother hand, some BCRi affect innate-immune cells, which might increasesusceptibility to infections. Here we evaluated the effect of idelalisib, aBCRi that targets PI3Kδ, on i) macrophage-phenotype and cytokine secretion, andii) the resistance of leukemic cells to venetoclax induced by activated T-cells.Humanmonocytes were cultured with GM-CSF+IFN-ɣ or M-CSF+IL-10 to obtain M1 or M2macrophages respectively. Immobilized anti-CD3 was used to activate T-cells. M1/M2-associatedmarkers, cell-viability and leukemic and T-cell activation were evaluated byflow 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 BTKi (n=6), while it impaired TNF-αsecretion induced by LPS without affecting macrophage viability (n=8,p<0.05). Idelalisib also impaired the up-regulation of CD40L on activated T-cells(n=8, p<0.05), and the consequent activation of leukemic cells, which showeda lower CD25 and CD86 expression (n=8, p<0.05). Interestingly, we also foundthat idelalisib reduced leukemic-cell resistance to venetoclax induced byactivated T cells (n=8, p<0.05).We found that idelalisib affects both macrophages and T-cells. This mightimpact on the anti-microbial immune response of treated patients, and alsosuggest that combination of idelalisib with venetoclax might be useful toovercome drug resistance.