PI3K signalling in B- and T-lymphocytes: new developments and therapeutic advances

Abstract

Synopsis Activation of phosphoinositide 3-kinase (PI3K) is a shared response to engagement of diverse types of transmembrane receptors. Depending on the cell type and stimulus, PI3K activation can promote different fates including proliferation, survival, migration and differentiation. The diverse roles of PI3K signaling are well illustrated by studies of lymphocytes, the cells that mediate adaptive immunity. Genetic and pharmacological experiments have shown that PI3K activation regulates many steps in the development, activation and differentiation of both B and T cells. These findings have prompted the development of PI3K inhibitors for the treatment of autoimmunity and inflammatory diseases. However, PI3K activation has both positive and negative roles in immune system activation. Consequently, while PI3K suppression can attenuate immune responses it can also enhance inflammation, disrupt peripheral tolerance and promote autoimmunity. An exciting discovery is that a selective inhibitor of the p110δ catalytic isoform of PI3K, CAL-101, achieves impressive clinical efficacy in certain B cell malignancies. A model is emerging in which p110δ inhibition disrupts signals from the lymphoid microenvironment, leading to release of leukemia and lymphoma cells from their protective niche. These encouraging findings have given further momentum to PI3K drug development efforts in both cancer and immune diseases.

Selective Inhibition of Phosphoinositide 3-Kinase p110α Preserves Lymphocyte Function*

“…Disruption of the MZ B cell subset is now recognized as a biomarker of p110␦ inhibition in mice (28,40). Genetic studies in mice suggest that a central signaling pathway governing MZ B cell development is initiated by CD19 on the cell surface, which signals via PI3K-p110␦ and AKT to suppress the transcription factor Foxo1 (40).…”

“…Genetic studies in mice suggest that a central signaling pathway governing MZ B cell development is initiated by CD19 on the cell surface, which signals via PI3K-p110␦ and AKT to suppress the transcription factor Foxo1 (40). Pharmacological inhibition of p110␦ using IC87114 reduces MZ B cell numbers but also disrupts their localization, with IgM hi /IgD lo B cells moving into the follicles (28).…”

Constitutive Akt1 signals attenuate B‐cell receptor signaling and proliferation, but enhance B‐cell migration and effector function

“…PI3K/Akt signaling plays a central role in B-cell activation and migration [11]. Genetic studies have shown that Akt1 and Akt2 are needed for the generation of MZ B cells and B1 B cells, but not of follicular B2 cells [12,13].…”

“…Important mediators downstream of Akt1 signaling include the tuberous sclerosis proteins 1 and 2 (TSC1/2), which regulate the activity of mTOR, a kinase controlling the activation of p70S6K and phosphorylation of ribosomal protein S6, and thus protein synthesis. Other prominent targets of Akt signaling are transcription factors of the NF-κB, NFAT, and FoxO families, which regulate the development, proliferation, and survival of B cells [7][8][9][10].PI3K/Akt signaling plays a central role in B-cell activation and migration [11]. Genetic studies have shown that Akt1 and Akt2 are needed for the generation of MZ B cells and B1 B cells, but not of follicular B2 cells [12,13].…”

Beta-Testing of PI3-Kinase Inhibitors: Is Beta Better?

“…Indeed, inhibiting p110α alone can reduce the growth of tumors containing PIK3CA mutations (3), but this approach is not effective in all solid tumors. No oncogenic mutations have been identified in the other class I PI3K isoforms; however, p110δ-selective inhibitors have proven effective in the clinic in certain forms of leukemia (4).…”