Enhancement of tumor cell susceptibility to natural killer cell activity through inhibition of the PI3K signaling pathway

Abstract

Natural killer (NK) cells are the primary effectors of the innate immune response against virus infected cells or cells that have undergone malignant transformation. NK cells recognize their targets through a complex array of activating and inhibitory receptors, which regulate the intensity of the effector response against individual target cells. However, many studies have shown that tumor cells can escape immune cell recognition through a variety of mechanisms, developing resistance to NK cell killing. Using a lentiviral shRNA library, we previously demonstrated that several common signaling pathways modulate susceptibility of tumor cells to NK cell activity. In this study, we focused on one of the genes (PI3KCB), identified in this genetic screen. The PI3KCB gene encodes an isoform of the catalytic subunit of PI3K called P110β. The PI3K pathway has been linked to diverse cellular functions, but has never been associated with susceptibility to NK cell activity. Gene silencing of PI3KCB resulted in increased susceptibility of several tumor cell lines to NK cell lytic activity and induced increased IFN-γ secretion by NK cells. Treatment of primary tumor cells with two different PI3K inhibitors also increased target cell susceptibility to NK cell activity. These effects are due, at least in part, to modulation of several activating and inhibitory ligands and appear to be correlated with PI3K signaling pathway inhibition. These findings identify a new and important role of PI3KCB in modulating tumor cell susceptibility to NK cells and open the way to future combined target immunotherapies.

New insights into the role of EMT in tumor immune escape

“…Aside from the context of EMT, other compounds have been tested that should be considered to enhance susceptibility to immune killer cells (Bommarito et al, 2016;He et al, 2013). Agents inhibiting the expression of PD-L1 through blockade of the AKT/PI3K/MTOR or the RAS/MEK signaling pathways, and more generally drivers of PD-L1 expression, could help sensitize cancer cells to immunotherapy at the onset in various tumor types (Alsuliman et al, 2015;Lastwika et al, 2016;Loi et al, 2016;Peng et al, 2016).…”

Drug-based cancer therapy to overcome immune resistance by steering tumor evolution

“…The immune-evading phenotype may be steered into pattern b by complementing the ICI + epidrug combination with a PI3K inhibitor specific for γ,δ-isoforms, such as duvelisib. This targeted agent enables the immune system to eliminate cancer cells that adopted evasion pattern a [14], while the residual population that survived by adopting pattern b may be partly eliminated by switching to a β-isoform-specific PI3K inhibitor, like GSK2636771 or AZD8186, that promotes elimination of phenotype b [15]. Thus, the proposed evolving therapy cycles the tumor back and forth between the two immune-evading phenotypes by alternating between the PI3K(γ,δ)-inhibitor and the PI3Kβ-inhibitor, so that the selected phenotype becomes susceptible in the next iteration ( Figure 2).…”

“…the TME, while PI3Kδ-inhibition in T regs is known to impair their maintenance and function within the TME [14]. On the other hand, PI3Kβ-inhibition in tumor cell impairs MHC-I-mediated antigen presentation, while stimulating the innate immune response of natural killers (NK), which are themselves responsive to cells lacking MHC-I antigen presentation [15].…”

“…The centrality of the PI3K-AKT-mTOR pathway in maintaining homeostasis in normal cells makes pan-PI3K inhibitors toxic and therapeutically inefficient, since the tolerable dose is insufficient to fulfill their inhibitory role [14]. Furthermore, non-isoform-specific PI3K inhibition is certain to cause counterproductive effects, since PI3Kβ-inhibition suppresses the adaptive immune response elicited by PI3K(γ,δ)-inhibition [15]. These opposing effects justify the need to use isoformspecific PI3K inhibitors in the proposed alternating manner.…”

Targeted therapy to annihilate the immune-evading phenotype in cancer evolution

“…Thus, we propose to block evasion route b through inhibition of the γ and δ isoforms of PI3K [10], so immunoediting funnels the evading phenotype into the first route. Subsequently, the selected resistant subpopulation of tumor cells may get wiped out in a second-line treatment based on a pan-PI3K inhibitor [11] (Figure 1).…”