PI3K-p110δ contributes to antibody responses by macrophages in chronic lymphocytic leukemia

Fc gamma receptor (Fc gamma R) signalling in monocyte derived macrophages from chronic lymphocytic leukaemia (CLL) patients is poorly understood. This signalling pathway is the key determinant of the ability of the macrophages to respond to therapeutic antibodies in current clinical use for CLL. Muted Fc gamma R signalling activity accompanies disease progression and results in resistance to therapeutic antibodies. The molecular mechanisms controlling Fc gamma R signalling and resistance are unknown. Here, we demonstrate that the class I phosphoinositide 3-kinase (PI3K) catalytic subunit p110 delta is essential for CLL-derived macrophages to respond to therapeutic antibodies. Inhibition of p110 delta in the macrophages reduces Fc gamma R-mediated antibody immune responses. Surprisingly, our studies indicated that Fc gamma R downstream signalling is independent of SYK and BTK activity. Thus, we show that Fc gamma R antibody responses occur via a previously unidentified p110 delta-dependent pathway, which is independent of the previously described SYK/BTK activation pathway. These data provide novel insights into the effectors of antibody responses. Our data also provide mechanistic insights into therapy resistance in CLL.