PI3Kδ inhibition modulates regulatory and effector T-cell differentiation and function in chronic lymphocytic...

Targeting B-cell receptor signaling using the PI3Kδ inhibitor idelalisib is a highly effective treatment option for relapsed/refractory chronic lymphocytic leukemia (CLL) patients. In addition to its direct impact on tumor cells, PI3Kδ inhibition can modulate the activity of regulatory T-cells (Tregs) resulting in enhanced anti-tumoral immune functions which may contribute to the success of PI3Kδ inhibitors in cancer therapy. The role of Tregs in CLL and their modulation by PI3Kδ inhibitors was so far poorly understood. Using the Eµ-TCL1 adoptive transfer model of CLL, we show that disease development induces the accumulation of activated and highly immunosuppressive Tregs. Depletion of CD25⁺ Tregs using anti-CD25 antibodies resulted in enhanced CD8⁺ T-cell activation, effector differentiation, and functional capacity. We further show that pharmacological inhibition of PI3Kδ effectively controlled disease and significantly decreased both CD25⁺ and CD25^- Treg numbers, proliferation and activation status in CLL-bearing mice. Nonetheless, this PI3Kδ-mediated decrease in Tregs did not translate into better CD8⁺ T-cell function, as PI3Kδ inhibition concomitantly abrogated T-cell receptor signaling in CD8⁺ T-cells leading to decreased activation, effector cell differentiation and proliferation. Collectively, these data highlight the strong immunomodulatory effects of PI3Kδ inhibitors in CLL and are of relevance for a rational design of idelalisib-based combination therapies in CLL.