The PI3K p110δ Isoform Inhibitor Idelalisib Preferentially Inhibits Human Regulatory T Cell Function

• DOI: 10.4049/jimmunol.1701703
• Publication Date: 2019-01-28T19:50:14Z
• Authors: Stalin Chellappa; Kushi Kushekhar; Ludvig A Munthe; Geir E Tjønnfjord; Einar M Aandahl; Klaus Okkenhaug; Kjetil Taskén
• Keywords: Idelalisib

Abstract In chronic lymphocytic leukemia (CLL), signaling through several prosurvival B cell surface receptors activates the PI3K pathway. Idelalisib is a highly selective (PI3Kδ) isoform-specific inhibitor effective in relapsed/refractory CLL and follicular lymphoma. However, severe autoimmune adverse effects association with use of idelalisib treatment CLL, particularly as first-line therapy, gave indications that may preferentially target suppressive function regulatory T cells (Tregs). On this background, we examined effect on human Tregs ex vivo respect to proliferation, TCR signaling, phenotype, function. Our results show are susceptible PI3Kδ inactivation using compared CD4+ CD8+ effector (Teffs) evident from anti-CD3/CD28/CD2–induced proliferation (order susceptibility [IC50]: Treg [.5 μM] > Teff [2.0 [6.5 μM]) acting at level AKT NF-κB phosphorylation. Moreover, altered their phenotype reduced against Teffs. Phenotyping patients treated supported our vitro findings. Collectively, data more dependent PI3Kδ-mediated This Treg-preferential could explain why produces by breaking Treg-mediated tolerance. balancing sensitivity versus insensitivity still potentially be exploited enhance inherent antitumor immune responses patients.