Profound blockade of T cell activation requires concomitant inhibition of different class I PI3K isoforms

Abstract

PI3K inhibitors have emerged as potential therapeutic tools for a variety of diseases, and thus, a vast array of compounds with specificity for different PI3K isoforms is being developed. Gaining knowledge about the contribution of the different isoforms to PI3K function will allow selecting the most appropriate inhibitor for each pathology. In this study, we have addressed the effect of PI3K inhibitors with specificity for different class I PI3K isoforms on primary human T cell activation. In particular, we have analyzed proliferation, expression of activation and differentiation markers, apoptosis induction, cytokine secretion and Akt phosphorylation in T cells stimulated in vitro with anti-CD3 and anti-CD28 monoclonal antibodies and cultured with either one of these compounds: p110β-specific inhibitor TGX-221, p110δ-specific inhibitor IC-87114, p110γ inhibitor AS-242525 or pan-class I PI3K inhibitor BKM120. Inhibition of any of the isoforms led to an impairment of T cell activation, mainly of cytokine secretion and granzyme B expression. However, only complete blockade of class I PI3K activity with the pan-class I inhibitor effectively abrogated T cell proliferation. These results indicate that these three p110 isoforms (β, δ and γ) take part in T cell activation, but all of them are dispensable for T cell proliferation.

Idelalisib and caffeine reduce suppression of T cell responses mediated by activated chronic lymphocytic leukemia cells

“…As PI3Kδ is widely expressed in leucocytes it is unknown whether this results from effects on the CLL cells, T cells, non-T cells or a combination of these. In agreement with other reports [53] neither caffeine nor Idelalisib affected the proliferation of PBMC cultured alone. It has been reported that broad PI3K inhibition can increase the susceptibility of T cells to suppression by cells such as Tregs [54].…”

Combined PI3K/Akt and Hsp90 targeting synergistically suppresses essential functions of alloreactive T cells and increases Tregs

“…In line with the Akti results, functional inhibition of PI3Kd by use of the specific pharmacological PI3Kd inhibitor Cal also reduced T allo proliferation. Thereby, a relatively high Cal concentration, which has been described previously to broaden the PI3Kd inhibitory effect also on the other PI3Kd [20], was necessary to achieve a considerable suppression of T allo proliferation, indicating that selective PI3Kd inhibition might be compensated, at least in parts, by activity of other PI3Kd, as already demonstrated for antigen-mediated cytokine production and proliferation of T cells [43,44]. Taken together, our results demonstrate an impact of PI3K/Akt activity on T allo proliferation in vitro but also indicate that neither Akt 1/2 nor PI3Kd inhibition alone might be sufficient for a substantial depletion of T allo in aGvHD patients and thus, suggest combination approaches.…”

Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development

“…On the other hand, BKM120 and BEZ235 induced a dose-dependent decrease in Th1/Th2 cytokine secretion, according to studies performed with PI3K [ 10 , 12 ] and mTOR inhibitors [ 28 , 29 ]. Once more, BEZ235 was more potent than BKM120 at intermediate doses.…”

“…In addition, it has been suggested that the beneficial effects observed in patients with chronic GvHD treated with tyrosine kinase inhibitors could be due, in part, to their ability to inhibit PI3K signaling in T cells [ 9 ]. However, few studies have evaluated the immunosuppressive effect of PI3K inhibitors on T lymphocytes [ 10 – 12 ] and their ability to prevent GvHD development [ 13 , 14 ]. Herein, we have analyzed the effects of two novel antitumor drugs, the pan-class I PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitor BEZ235, on T cell activation and evaluated the utility of BEZ235 in a murine model of GvHD.…”