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

Abstract

Chronic lymphocytic leukemia (CLL) is associated with T cell dysfunction. Activated CLL cells are found within the lymphoid tumor micro-environment and overcoming immuno-suppression induced by these cells may improve anti-CLL immune responses. However, the mechanisms by which activated CLL cells inhibit T cell responses, and reagents targeting such mechanisms have not been identified. Here we demonstrate that the ability of in vitro activated CLL cells to suppress T cell proliferation is not reversed by the presence of ecto-nuclease inhibitors or blockade of IL-10, PD-1 and CTLA-4 pathways. Caffeine is both an adenosine receptor antagonist and a phosphatidylinositol-3-kinase, p110δ (PI3Kδ) inhibitor and, at physiologically relevant levels, significantly reversed suppression. Significant reversal of suppression was also observed with the PI3Kδ specific inhibitor Idelalisib but not with adenosine receptor specific antagonists. Furthermore, addition of caffeine or Idelalisib to activated CLL cells significantly inhibited phosphorylation of AKT, a downstream kinase of PI3K, but did not affect CLL viability. These results suggest that caffeine, in common with Idelalisib, reduces the immuno-suppressive activity of activated CLL cells by inhibiting PI3Kδ. These findings raise the possibility that these compounds may provide a useful therapeutic adjunct by reducing immuno-suppression within the tumor micro-environment of CLL.

Tumor microenvironment: a prospective target of natural alkaloids for cancer treatment

“…Caffeine reduces the immunosuppressive activity of activated lymphocytes by inhibiting phosphatidylinositol kinase δ. These findings strengthen the fact that Caffeine may provide an effective therapy by reducing immunosuppression in the CLL tumor microenvironment [52]. Piperine impedes the progression of TNBS-induced colitis through regulating the nuclear factors of kappa light polypeptide gene enhancers in the B cell inhibitor-α/NF-κB signal pathway, to inhibit the overexpression of proinflammatory cytokines (TNF-α and ILs), cyclooxygenase-2(COX-2), colonic inducible nitric oxide synthase (iNOs), and oxidative-nitrous acid stress [53,54] (Fig.…”

PI3K p110δ inactivation antagonizes chronic lymphocytic leukemia and reverses T cell immune suppression

“…Emerging evidence has shown an immune-activating effect with pharmacologic p110δ inhibitors (16,(30)(31)(32). When given as initial therapy for CLL, idelalisib causes frequent hepatotoxicity associated with higher CD8 + T cell infiltration in the liver and lower numbers of Tregs in the blood (16).…”

“…Murine and human CD8 + T cells treated with idelalisib in vitro exhibit an undifferentiated phenotype and persist longer after transfer into tumor-bearing mice, which leads to better antitumor immunity in both murine syn geneic and human xenograft tumor models (32). Coculture of CLL cells with T cells in the presence of idelalisib reduces CLL-induced T cell suppression (30). However, inhibitors have variable specificity, and the immune-activating effects of idelalisib could be confounded by the lowered disease burden.…”

Combination Strategies for Immune-Checkpoint Blockade and Response Prediction by Artificial Intelligence

“…In line with this, another BCR signaling inhibitor, acting on PI3K (idelalisib) was also shown to decrease proliferation and effector function of Tregs in vitro. This effect was mediated by inhibition of the PI3K/Akt/nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB) axis, whereupon a synergistic effect of idelalisib with immune-checkpoint inhibition was proposed [61,62].…”