La phosphoinositide 3-kinase p110δ (PI3Kδ) est principalement exprimée dans les cellules hématopoïétiques et son inhibiteur, l'idélalisib est approuvé pour le traitement de la leucémie et du lymphome. Cependant, la fonction de cette isoforme dans les cellules non hématopoïétiques reste insaisissable. Dans cette étude, nous rapportons que la formation des canalicules biliaires est dépendante de l’activité de la PI3Kδ lors de la culture en 3D de cellules de carcinome hépatocellulaire. Une étude in-vitro reposant sur la différenciation de cellules souches embryonnaires humaines en hépatocytes révèle que la PI3Kδ est enrichie dans les cellules souches et que son expression diminue au fur et à mesure que les cellules se différencient. Lorsqu’elle est surexprimée, la PI3Kδ reprogramme ces cellules en cellules ressemblant à des cellules souches formant des rosettes polarisées et perdant des marqueurs d’hépatocytes pour acquérir des traits de cholangiocytes. Dans le foie murin, la réexpression de la PI3Kδ entraine des modifications de la morphologie de cellules jouxtant la veine porte, ainsi que l’augmentation de l’expression du gène codant pour EpCAM. Cette reprogrammation dépendante de la PI3Kδ est associée à l'activation de la voie de Notch et requiert l'activation de la protéine Src. Enfin, la PI3Kδ est exprimée dans les lignées cellulaires dérivées d’hépatoblastome humain et le traitement des souris par l’idélalisib diminue la taille des tumeurs formées par les PDX d’hépatoblastome. La PI3Kδ représente donc une cible thérapeutique prometteuse dans ce cancer pédiatrique avec des caractéristiques de cellules souches. / The phosphoinositide 3-kinase p110δ (PI3Kδ) is primarily expressed in the hematopoietic cells and its inhibitor, Idelalisib, is approved for leukemia and lymphoma treatments. Nevertheless, the function of PI3Kδ in the non-hematopoietic cells is still elusive. Here we report that the formation of bile canaliculi is dependent on the PI3Kδ activity using hepatocellular carcinoma (HCC) cells grown in a 3D culture. In-vitro study based on hepatocytes differentiation from human Embryonic Stem Cell (hESC) highlights that PI3Kδ is enriched in hESC and increasingly reduces over time while cells are differentiating. When PI3Kδ is overexpressed, it reprograms those cells into stem-like cells forming polarized rosette structures and losing hepatocyte markers to gain cholangiocyte characteristics. These changes were observed in mice liver overexpressing PI3Kδ. The aforementioned reprogramming, dependent on PI3Kδ, is associated with the Notch pathway activation and requires the Src protein activation. Finally,PI3Kδ is expressed in hepatoblastoma cell lines and idelalisib efficiently reduces tumor size formed by patient derived xenograft (PDX). Therefore, PI3Kδ represents a promising therapeutic target for this pediatric cancer with stem cell features.

Yes / Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1–3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity. / Research Development Fund Publication Prize Award winner, May 2022.