Effect of IL-2R beta-binding cytokines on costimulatory properties of chronic lymphocytic leukaemia cells: implications for immunotherapy.
Weak immunogenicity of chronic lymphocytic leukaemia (CLL) cells may contribute to disease progression and inhibit the effectiveness of immunotherapies, such as vaccines. Agents that can enhance the antigen presenting capabilities of CLL cells might then help to improve the clinical results of immunotherapies. This study investigated the effects of the common gamma chain-binding cytokines, interleukin (IL)-2 and IL-15, on costimulatory properties of primary CLL cells from 51 patients. IL-2 improved the ability of CLL cells to stimulate T cell proliferation and increased the expression of costimulatory molecules (particularly CD80) in a dose-dependent fashion, especially in CLL cells with weak expression of CD38. CD80 and CD86 induction by IL-2 were positively regulated through the mitogen-activated protein kinase pathway, while CD86 expression was negatively regulated through Janus kinase pathways. However, further activation with protein kinase C agonists was required for IL-2 activated CLL cells to stimulate autologous T cells sufficiently to clear bystander CLL cells from mixed lymphocyte responses. IL-15 had similar effects on the costimulatory properties of CLL cells. These results suggest a role for IL-2, or IL-15, in immunotherapeutic strategies for CLL.
Spaner
David E
DE
Division of Molecular and Cellular Biology, Research Institute, Sunnybrook and Women's College Health Sciences Center, Toronto M4N 3M5, Canada. spanerd@srcl.sunnybrook.utoronto.ca
Hammond
Caitlin
C
Mena
Jenny
J
Shi
Yonghong
Y
D036541:ADP-ribosyl Cyclase / Q000276:immunology; D051997:ADP-ribosyl Cyclase 1; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology*; D051940:B7-2 Antigen; D049109:Cell Proliferation; D003601:Cytotoxicity Tests, Immunologic; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods*; D019409:Interleukin-15 / Q000627:therapeutic use; D007376:Interleukin-2 / Q000627:therapeutic use; D053646:Interleukin-2 Receptor beta Subunit; D007378:Interleukins / Q000627:therapeutic use*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000628:therapy*; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D008875:Middle Aged; D018123:Receptors, Interleukin / Q000378:metabolism*
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; C508020:IL2RB protein, human; D019409:Interleukin-15; D007376:Interleukin-2; D053646:Interleukin-2 Receptor beta Subunit; D007378:Interleukins; D008562:Membrane Glycoproteins; D018123:Receptors, Interleukin; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1