Effects of novel isoform-selective phosphoinositide 3-kinase inhibitors on natural killer cell function

Area of Science:

• Immunology
• Oncology
• Cell Signaling

Background:

• Phosphoinositide 3-kinases (PI3Ks) are key regulators of cellular processes and are implicated in cancer development.
• The PIK3CA gene, encoding the p110α isoform of PI3K, is frequently mutated in various human cancers.
• The role of specific PI3K isoforms, particularly p110α, in natural killer (NK) cell function remains largely unexplored.

Purpose of the Study:

• To investigate the functional role of p110α and other class I PI3K isoforms in NK cell-mediated anti-tumor activity.
• To assess the impact of p110α-selective inhibitors on NK cell cytotoxicity, signaling, and cytokine production.
• To evaluate the in vivo effects of a p110α inhibitor on NK cell populations in mice.

Main Methods:

• Utilized investigational inhibitors targeting different class I PI3K isoforms (pan-PI3K, p110α-selective, p110δ-selective).
• Assessed NK cell-mediated cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) against tumor cells.
• Measured PI3K signaling output (AKT phosphorylation), IFN-γ production, and chemokine release in NK cells.
• Administered a p110α inhibitor (MLN1117) orally to mice and analyzed NK cell subset maturation and commitment.

Main Results:

• Pan-PI3K inhibition significantly impaired NK cell cytotoxicity and ADCC, while p110α-selective inhibitors had no significant effect.
• p110α inhibition showed modest effects on PI3K signaling (AKT phosphorylation) in stimulated NK cells.
• IFN-γ production and chemokine release were blocked by pan-PI3K inhibitors and partially reduced by p110δ inhibitors, with minimal impact from p110α inhibitors.
• Oral administration of the p110α inhibitor MLN1117 had negligible effects on NK cell subset maturation and commitment in vivo.

Conclusions:

• Selective p110α inhibitors do not impair NK cell-mediated cytotoxicity or key effector functions.
• Targeting PIK3CA mutant tumors with p110α inhibitors may preserve NK cell immunosurveillance and anti-tumor functions.
• These findings support the therapeutic strategy of using p110α inhibitors in oncology while maintaining NK cell-mediated anti-tumor immunity.