Solid tumor cell-intrinsic function of PI3Kdelta

PI3Kdelta is a predominantly leukocyte-enriched class I PI3K consisting of the p110delta catalytic subunit (encoded by PIK3CD ) and most commonly the p85alpha regulatory subunit (encoded by PIK3R1 ). PI3Kdelta is an important regulator of B-cell function and has been the target of extensive drug development efforts for B-cell malignancies, with multiple inhibitors approved for this indication. Based on our pre-clinical studies, PI3Kdelta inhibition is now also emerging as an immunotherapy approach for solid tumours. Regulatory T-cells (Treg) are exquisitely sensitive to PI3Kdelta inhibition, therefore pharmacological PI3Kdelta inhibitors preferentially target the Tregs, rebalancing the immune system in favour of an effector T cell-mediated anti-tumour immune response. This concept is currently under investigation in clinical trials in uveal melanoma and non-small cell lung cancer. Notably, we and others have also observed multiple solid tumour types including glioblastoma, melanoma, breast cancer, prostate cancer, neuroblastoma and hepatocellular carcinoma also express wild-type PIK3CD , often at much higher levels than their non-transformed cell types of origin. Some studies suggest PI3Kdelta promotes proliferation in these tumour cells, but this remains unclear with the potential that inhibitors were used at non-PI3Kdelta-specific concentrations, and these findings are not consistently confirmed with genetic approaches. This raises the questions of what function PI3Kdelta plays in solid tumours and how the use of PI3Kdelta inhibitors for immunotherapy will affect the tumour cells themselves via inhibition of cell-intrinsic PI3Kdelta. Using highly-selective PI3Kdelta inhibitors and CRISPR-Cas9-mediated PIK3CD deletion in solid tumour cell lines, we demonstrate that PI3Kdelta inhibition does not affect cell proliferation in these models. However, through both in vitro and xenograft studies, we have identified cancer-relevant roles for PI3Kdelta in solid tumours, the implications of which will be presented. Our data suggest the solid tumour cell-intrinsic PI3Kdelta expression should be considered to inform PI3Kdelta-targeting immunotherapy studies.