Cancer Cell Biology

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

  1. Daniela Rožková1,†,*,
  2. Linda Novotná1,
  3. Robert Pytlík2,
  4. Ivana Hochová3,
  5. Tomáš Kozák4,
  6. Jiřina Bartůňková1,
  7. Radek Špíšek1

Article first published online: 14 AUG 2009

DOI: 10.1002/ijc.24832

Issue

International Journal of Cancer

International Journal of Cancer

Volume 126, Issue 5, pages 1132–1143, 1 March 2010

Additional Information

How to Cite

Rožková, D., Novotná, L., Pytlík, R., Hochová, I., Kozák, T., Bartůňková, J. and Špíšek, R. (2010), Toll-like receptors on B-CLL cells: expression and functional consequences of their stimulation. Int. J. Cancer, 126: 1132–1143. doi: 10.1002/ijc.24832

Author Information

  1. 1

    Institute of Immunology, Charles University, 2nd Faculty of Medicine, University Hospital Motol, Prague, Czech Republic

  2. 2

    First Department of Medicine, Charles University, 1st Faculty of Medicine, General University Hospital, Prague, Czech Republic

  3. 3

    Department of Hematology, Charles University, 2nd Faculty of Medicine, University Hospital Motol, Prague, Czech Republic

  4. 4

    Department of Clinical Hematology, Charles University, 3rd Faculty of Medicine, University Hospital Královské Vinohrady, Prague, Czech Republic

  1. †

    Fax: +420-2-24-43-59-62

*Department of Immunology, 2nd Medical School, Charles University, V Úvalu 84, Prague 5 - Motol, 15006, Czech Republic

Publication History

  1. Issue published online: 27 DEC 2009
  2. Article first published online: 14 AUG 2009
  3. Accepted manuscript online: 14 AUG 2009 12:00AM EST
  4. Manuscript Accepted: 6 AUG 2009
  5. Manuscript Received: 8 JUN 2009

Funded by

  • Grant Agency of Czech Republic. Grant Number: 310/08/P353
  • Ministry of Education. Grant Number: MSM 0021620812

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Keywords:

  • B-Cell chronic lymphocytic leukemia;
  • toll-like receptors;
  • tumor immunology;
  • B-cells;
  • cancer immunotherapy

Abstract

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.

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