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.
Highlights
B-cell chronic lymphocytic leukemia (CLL) is associated with a profound immuno-suppression which results in both impaired anti-tumor responses and increased susceptibility to infection [1]
Analysis of B7 family member expression by CLLAct demonstrated that, relative to CLL cells cultured in media alone, levels of CD80, CD86, CD274 (PDL-1) and CD276 (B7H3) were all significantly increased (Fig 1A)
As we reported previously we did not observed increased IL-10 release by CLLAct and, in keeping with those findings, addition of blocking IL-10 mAb did not reduce suppression induced by CLLAct (Fig 1B)
Summary
B-cell chronic lymphocytic leukemia (CLL) is associated with a profound immuno-suppression which results in both impaired anti-tumor responses and increased susceptibility to infection [1]. It has become recognised that, within lymphoid tissue, the complex interaction of CLL cells with the tumor micro-environment (TME) provides signals necessary to sustain tumor progression and immune evasion [2, 3, 9]. Within the so-called pseudo follicles of the TME activated CLL cells are found in close contact with activated T cells, and it is thought this interaction is critical for CLL progression [10,11,12]. It is unclear how activated CLL cells suppress anti-tumor responses
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