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. Author manuscript; available in PMC: 2022 Jul 20.
Published in final edited form as: Nat Rev Drug Discov. 2021 Jun 14;20(10):741–769. doi: 10.1038/s41573-021-00209-1

Figure 6 – Multi-pronged anti-cancer activity of PI3Kδ inhibition in cancer.

Figure 6 –

a. Proposed triple mode-of-action of PI3Kδ inhibition in CLL: (1) a cancer-cell intrinsic impact, with PI3Kδ dampening signalling by the BCR and a range of cytokines, chemokines, co-stimulatory molecules and adhesion receptors; (2) inhibition of stromal cells that support the leukaemic cells, such as myeloid-derived nurse-like cells, mesenchymal fibroblast-like cells and leukaemia-associated T-cells, and (3) a host anti-leukaemia adaptive immune response, as a consequence of dampening of Treg function upon PI3Kδ inhibition.

b. Documented effects of PI3Kδ inhibition in FL: (1) a cancer-cell intrinsic impact, with PI3Kδ dampening signalling by the BCR, the CD40/CD40L pathway as well as restoration of FL cell dependence on the BCL2 anti-apoptotic protein, resulting in a predisposition to FL cell death and sensitivity to BLC2 inhibitors; (2) dampening of recruitment of T-follicular helper cells and Treg cells through downmodulation of the CCL22 chemokine; and downregulation of proteins involved in B–T-cell synapses, leading to an inefficient crosstalk between FL cells and T-follicular helper cells; (3) dampening of follicular dendritic cell-FL interactions related to angiogenesis, cell adhesion and transendothelial migration in FL patients that show a clinical response to PI3Kδ inhibition. (4) a host anti-leukaemia adaptive immune response, as a consequence of dampening of Treg function upon PI3Kδ inhibition. Such a PI3Kδ-inhibition induced immune response has to be formally documented in FL.

c. Effect of PI3Kδ inhibition in solid tumours: (1) a cancer cell-intrinsic impact: some solid tumours (such as breast and melanoma) express high levels of PI3Kδ which may provide sensitivity to PI3Kδ inhibition. (2) dampening of the immuno-suppressive effects of MDSCs and macrophages, and dampening of cancer-stimulating fibroblasts and macrophages, and (3) preferential inhibition of Treg cells, allowing a CD8+ T-cell immune response to develop. The question marks in the figure indicate that the role of PI3Kδ in the indicated responses requires further validation, with inhibition of PI3Kγ likely to have a stronger suppressive impact on macrophages than inhibition of PI3Kδ, and blockade of PI3Kα and/or PI3Kβ having a stronger impact than PI3Kδ inhibition on fibroblasts.