title: 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.
authors.affiliation: Haematology Research Group, Christchurch Hospital, Christchurch, New Zealand.|Pathology Department, University of Otago, Christchurch, New Zealand.
authors.forename: Barry D
authors.initials: BD
authors.lastname: Hock
authors.affiliation: Pathology Department, University of Otago, Christchurch, New Zealand.|Haematology Department, Christchurch Hospital, Christchurch, New Zealand.
authors.forename: Sean A
authors.initials: SA
authors.lastname: MacPherson
authors.affiliation: Haematology Research Group, Christchurch Hospital, Christchurch, New Zealand.|Pathology Department, University of Otago, Christchurch, New Zealand.
authors.forename: Judith L
authors.initials: JL
authors.lastname: McKenzie
mesh_terms: D002110:Caffeine / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011687:Purines / Q000008:administration & dosage*; D052999:Quinazolinones / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; D002110:Caffeine; D019869:Phosphatidylinositol 3-Kinases; C552946:idelalisib