Toll‐like receptors on B‐CLL cells: expression and functional consequences of their stimulation

• Published in: International journal of cancer 2010-03, Vol.126 (5), p.1132-1143
• Main Authors: ROZKOVA, Daniela, NOVOTNA, Linda, PYTLIK, Robert, HOCHOVA, Ivana, KOZAK, Tomáš, BARTUNKOVA, Jiřina, SPISEK, Radek
• Format: Article
• Language: English
• Subjects: ADP-ribosyl Cyclase 1 - biosynthesis; Aged; Aged, 80 and over; Biological and medical sciences; B‐Cell chronic lymphocytic leukemia; B‐cells; cancer immunotherapy; Cell Proliferation; Cells, Cultured; Female; Flow Cytometry; Hematologic and hematopoietic diseases; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - immunology; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocyte Activation - immunology; Male; Medical sciences; Middle Aged; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Toll-Like Receptors - agonists; Toll-Like Receptors - immunology; Toll-Like Receptors - metabolism; toll‐like receptors; tumor immunology; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.24832

Toll‐like receptor (TLR) stimulation plays a crucial role in the homeostasis of human B cells. We investigated the expression of TLRs 1–9 on the cells of B‐cell chronic lymphocytic leukemia (B‐CLL) and analyzed the functional consequences of TLR stimulation on leukemic cells. We showed that B‐CLL cells express similar set of TLRs as memory B cells of healthy donors, i.e. TLR‐1, TLR‐2, TLR‐6, TLR‐7 and TLR‐9. However, in contrast to memory B cells, B‐CLL cells lack TLR‐4 expression. Expression of TLRs correlates with their capacity to respond to specific TLR agonists. At the level of phenotype, ODN2006 (TLR‐9 agonist) is the most potent stimulus. B‐CLL cells also respond to the stimulation with loxoribine, Pam3CSK4 and MALP‐2 (TLR‐7, TLR1/TLR2 and TLR2/TLR6 agonists, respectively). TLR‐7 and TLR‐9 stimulation induces production of IL‐6 and TNFα. In 47% of tested patients, treatment with ODN2006, MALP‐2 and Pam3CSK4 reduced leukemic cells survival. Stimulation of B‐CLL cells with TLR‐9 agonists, loxoribine, MALP‐2 and Pam3CSK4 induces significant proliferation. We report that TLR stimulation induces expression of CD38, a negative prognostic marker, on B‐CLL cells. Expression of CD38 is induced by direct stimulation of B‐CLL cells through TLR‐7 and TLR‐9 or CD38 can be induced on B‐CLL cells indirectly by a soluble factor induced in non‐B‐CLL cells after stimulation with TLR‐2, TLR‐3 or TLR‐5 agonists; the nature of this factor remains unknown. Our results argue for cautious evaluation of immunointervention strategies based on the administration of TLR agonists in the treatment of B‐CLL as their effects on B‐CLL cells may be tumor promoting as well as tumor suppressing.