Abstract
PI3K is one of the most frequently mutated genes in cancers and has been the target of numerous anticancer therapies. With the additional development of therapeutics that mobilize the immune system, such as Abs with effector functions, bispecific Abs, and checkpoint inhibitors, many small molecule inhibitors that target PI3K are being combined with these immunomodulatory treatments. However, the PI3K pathway is also essential for lymphocyte function, and the presence of the PI3K inhibitor may render the immunomodulatory therapeutic ineffective in these combinatorial treatments. Therefore, therapeutics with enhanced activity, such as afucosylated Abs, which promote signaling and function, may be ideal in these types of treatments to offset the negative effect of PI3K inhibitors on immune cell function. Indeed, we show that afucosylated Abs can counterbalance these inhibitory effects on FcγRIIIa-driven signaling in human NK cells to produce signals similar to cells treated only with fucosylated Ab. Furthermore, NK cell activation, degranulation, chemokine/cytokine production, and Ab-dependent cellular cytotoxicity were similar between inhibitor-treated, afucosylated Ab-stimulated NK cells and cells activated only with its fucosylated counterpart. To our knowledge, these studies also identified a previously undefined role for phospho-S6 in human NK cells. In this study, a kinetic delay in PI3K-driven phosphorylation of S6 was observed to control transcription of the temporally regulated production of IFN-γ and TNF-α but not MIP-1α, MIP-1β, and RANTES. Together, these studies demonstrate the importance of the PI3K pathway for S6 phosphorylation in human NK cells and the need to combine PI3K inhibitors with therapeutic molecules that enhance immunomodulatory function for anticancer therapies.