THE IMPAIRMENT OF ANTITUMOR CYTOTOXIC ACTIVITY OF DENDRITIC CELLS IN PATIENTS WITH MALIGNANT LYMPHOMA DUE TO THE ALTERED EXPRESSION OF TUMOR NECROSIS FACTOR ALPHA
Abstract
Recent research revealed dendritic cells (DCs) to have direct antitumor cytotoxic activity and to inhibit the growth and proliferation of tumor cells in vitro. The aim of the present study was to investigate the association between the cytotoxic activity of dendritic cells generated in the presence of interferon alpha (IFN-DCs) and TNFα expression by IFN-DCs in patients with malignant lymphomas. It was shown that IFN-DCs of malignant lymphoma patients possessed low cytotoxic activity against tumor cell line HEp-2 associated with low expression of transmembrane TNFα (tmTNFα) and high level of soluble TNFα (sTNFα) secretion. Reduced DC cytotoxic activity and low tmTNFα expression on DC surface were observed mainly in Hodgkin’s lymphoma patients. In contrast, IFN-DCs of patients with non-Hodgkin lymphoma were endowed with the ability to lysis of HEp-2 cells and tmTNFα molecule expression was similar to that in IFN-DCs from healthy donors. It was determined that the increase of expression of tmTNFα molecule on lymphoma patient IFN-DCs induced by the addition of TNFα-converting enzyme inhibitor into IFN-DC cultures was associated with the enhancement of IFN-DC cytotoxic activity against HEp-2 cells.
Supporting agencies: dendritic cells; interferon alpha; lymphomas; tumor necrosis factor alpha
About the Authors
T. V. Tyrinova
Research Institute of Fundamental and Clinical Immunology, Novosibirsk
Russian Federation
Russian Federation
Tyrinova Tamara Viktorovna, PhD, research fellow, Laboratory of Cellular Immunotherapy.
Phone: +7 (383) 228-21-01. E-mail: tyrinova@bk.ru. SPIN-code: 1535-6493
O. Yu. Leplina
Research Institute of Fundamental and Clinical Immunology, Novosibirsk
Russian Federation
Russian Federation
Lepina Olga Yurievna, MD, DSc, Leading researcher, Laboratory of Cellular Immunotherapy.
Phone: +7 (383) 228-21-01. E-mail: oleplina@mail.ru. SPIN-code: 2204-9718
M. A. Tikhonova
Research Institute of Fundamental and Clinical Immunology, Novosibirsk
Russian Federation
Russian Federation
Tikhonova Marina Alexandrovna, Senior research fellow, Laboratory of Cellular Immunotherapy.
Phone: +7 (383) 228-21-01. E-mail: martix-59@mail.ruD. S. Batorova
Research Institute of Fundamental and Clinical Immunology, Novosibirsk
Russian Federation
Russian Federation
Batorova Daria Sergeevna, hematologist, Hematology Department with Bone Marrow Transplantation Unit.
Phone: +7 (383) 228-59-56. E-mail: sugar1983@mail.ruG. Yu. Ushakova
Research Institute of Fundamental and Clinical Immunology, Novosibirsk
Russian Federation
Russian Federation
Ushakova Galina Yurievna, hematologist, Hematology Department with Bone Marrow Transplantation Unit.
Phone: +7 (383) 228-59-56. E-mail: bmt-novosibirsk@mail.ru
V. V. Sergeevicheva
Research Institute of Fundamental and Clinical Immunology, Novosibirsk
Russian Federation
Russian Federation
Sergeevicheva Bera Vasilievna, MD, PhD, Hematology Department with Bone Marrow Transplantation Unit.
Phone: +7 (383) 228-59-56. E-mail: verden@bk.ru. SPINcode: 5507-1870
S. A. Sizikova
Research Institute of Fundamental and Clinical Immunology, Novosibirsk
Russian Federation
Russian Federation
Sizikova Svetlana Anatolievna, MD, PhD, Hematology Department with Bone Marrow Transplantation Unit.
Phone: +7 (383) 228-59-56. E-mail: bmt-novosibirsk@mail.ruI. V. Kryuchkova
Research Institute of Fundamental and Clinical Immunology, Novosibirsk
Russian Federation
Russian Federation
Kruchkova Irina Valentinovna, MD, PhD, Head of Hematology Department with Bone Marrow Transplantation Unit.
Phone: +7 (383) 228-59-56. E-mail: irina_ici@ mail.ru. SPIN-code: 7668-3559A. A. Ostanin
Research Institute of Fundamental and Clinical Immunology, Novosibirsk
Russian Federation
Russian Federation
Ostanin Alexandr Anatolievich, MD, Professor, Principal Investigator, Laboratory of Cellular Immunotherapy.
Phone: +7 (383) 228-21-01. E-mail: ct_lab@mail.ru. SPIN-code: 3199-0970
E. R. Chernykh
Research Institute of Fundamental and Clinical Immunology, Novosibirsk
Russian Federation
Russian Federation
Chernykh Elena Removna, Professor, Corresponding Member of RAS, Head of Cellular Immunotherapy Laboratory.
E-mail: ct_lab@mail.ru. SPIN-code: 8957-0362References
1. Leplina O.Yu., Nasonova G.V., Tikhonova M.A., Kryuchkova I.V., Lisukov I.A., Ostanin A.A., Chernykh E.R. IFN-α-induced dendritic cells in patients with multiple myeloma // Sibirskij onkologicheskij zhurnal. 2009. № 6. P. 37–43. [in Russian]
2. Banchereau J., Steinman R.M. Dendritic cells and the control of immunity // Nature. 1998. Vol. 392 (6673). P. 245–252.
3. Black R.A., Rauch C.T., Kozlosky C.J., Peschon J.J., Slack J.L., Wolfson M.F., Castner B.J., Stocking K,L., Reddy P., Srinivasan S., Nelson N., Boiani N., Schooley K.A., Gerhart M., Davis R., Fitzner J.N., Johnson R.S., Paxton R.J., March C.J., Cerretti D.P. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells // Nature. 1997. Vol. 385 (6618). P. 729–733.
4. Brennan F.M., Green P., Amjadi P., Robertshaw H.J., AlvarezIglesias M., Takata M. Interleukin-10 regulates TNF-α-converting enzyme (TACE/ADAM-17) involving a TIMP-3 dependent and independent mechanism // Eur. J. Immunol. 2008. Vol. 38. P. 1106–1117. doi: 10.1002/eji.200737821.
5. Gruss H.J. Molecular, structural, and biological characteristics of the tumor necrosis factor ligand superfamily // Int. J. Clin. Lab. Res. 1996. Vol. 26 (3). P. 143–159.
6. Healy F., Rees R.C., Hancock B.W. An assessment of natural cellmediated cytotoxicity in patients with malignant lymphoma // Eur. J. Cancer Clin. Oncol. 1985. Vol. 21 (7). P. 775–783.
7. Janjic B.M., Lu G., Pimenov A., Whiteside T.L., Storkus W.J., Vujanovic N.L. Innate direct anticancer effector function of human immature dendritic cells. I. Involvement of an apoptosis-inducing pathway // J. Immunol. 2002. Vol. 168 (4). P. 1823–1830.
8. Jhaver K., De A., Advani S., Nadkarni J. Production of interleukin-1 and tumour necrosis factor in non-Hodgkin’s lymphoma patients // Cancer Immunol. Immunother. 1991. Vol. 34 (2). P. 123–127.
9. Kriegler M., Perez C., DeFay K., Albert I., Lu S.D. A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF // Cell. 1988. Vol. 53 (1). P. 45–53.
10. Le Gall S.M., Maretzky T., Issuree P.D., Niu X.D., Reiss K., Saftig P., Khokha R., Lundell D., Blobel C.P. ADAM17 is regulated by a rapid and reversible mechanism that controls access to its catalytic site // J. Cell Sci. 2010. Vol. 123. P. 3913–3922. doi: 10.1242/jcs.069997.
11. Leplina O., Tyrinova T., Tikhonova M., Shevela E., Stupak V., Mishinov S., Pendyurin I., Sadovoy M., Ostanin A., Chernykh E. Direct Antitumor Activity of Interferon-Induced Dendritic Cells of Healthy Donors and Patients with Primary Brain Tumors // Glioma – Exploring Its Biology and Practical Relevance. NTECH Open Access Publisher. 2011. P. 325–342.
12. Lu G., Janjic B.M., Janjic J., Whiteside T.L., Storkus W.J., Vujanovic N.L. Innate Direct Anticancer Effector Function of Human Immature Dendritic Cells. II. Role of TNF, Lymphotoxin-α1β2, Fas ligand, and TNF-related apoptosis-inducing ligand // J. Immunol. 2002. Vol. 168. P. 1831–1839. doi: 10.4049/jimmunol.168.4.1831.
13. Luettiq B., Decker T., Lohmann-Matthes M.L. Evidence for the existence of two forms of membrane tumor necrosis factor: an integral protein and a molecule attached to its receptor // J. Immunol. 1989. Vol. 143 (12). P. 4034–4038.
14. Mehta B.A., Advani S.H., Nadkarni S.J. Natural killer activity and antibody-dependent cellular cytotoxicity in patients with non-Hodgkin’s lymphoma // Neoplasma. 1988. Vol. 35 (1). P. 61–68.
15. Moreira-Tabaka H., Peluso J., Vonesch J.L., Hentsch D., Kessler P., Reimund J.M., Dumont S., Muller C.D. Unlike for human monocytes after LPS activation, release of TNF-α by THP-1 cells is produced by a TACE catalytically different from constitutive TACE // PLoS ONE. 2012. Vol. 7 (3). e34184. doi:10.1371/journal.pone.0034184.
16. O’Callagha D.J., O’Dea K.P., Takata M., Gordon A.C. Monocyte TACE activity profile during sepsis and systemic inflammatory response syndrome // Intensive Care Medicine Experimental. 2014. Vol. 2 (Suppl. 1). P. 6. doi: 10.1186/2197-425X-2-S1-P6.
17. Sappino A.P., Seelentag W., Pelte M.F., Alberto P., Vassalli P. Tumor necrosis factor/cachectin and lymphotoxin gene expression in lymph nodes from lymphoma patients // Blood. 1990. Vol. 75 (4). P. 958–962.
18. Tyrinova T.V., Leplina O.Y., Mishinov S.V., Tikhonova M.A., Shevela E.Y., Stupak V.V., Pendyurin I.V., Shilov A.G., Alyamkina E.A., Rubtsova N.V., Bogachev S.S., Ostanin A.A., Chernykh E.R. Cytotoxic activity of ex-vivo generated IFNα-induced monocyte-derived dendritic cells in brain glioma patients // Cell. Immunol. 2013. Vol. 284 (1–2). P. 146–153. doi: 10.1016/j.cellimm.2013.07.013.
19. Vandenabeele P., Declercq W., Beyaert R., Fiers W. Two tumor necrosis factor receptors: structure and function // Trends Cell. Biol. 1995. Vol. 5 (10). P. 392–399.
20. Vanderheyde N., Vandenabeele P., Goldman M., Willems F. Distinct mechanisms are involved in tumoristatic and tumoricidal activities of monocyte-derived dendritic cells // Immunol. Lett. 2004. Vol. 91 (2–3). P. 99–101.
Review
For citations:
Tyrinova T.V., Leplina O.Yu., Tikhonova M.A., Batorova D.S., Ushakova G.Yu., Sergeevicheva V.V., Sizikova S.A., Kryuchkova I.V., Ostanin A.A., Chernykh E.R. THE IMPAIRMENT OF ANTITUMOR CYTOTOXIC ACTIVITY OF DENDRITIC CELLS IN PATIENTS WITH MALIGNANT LYMPHOMA DUE TO THE ALTERED EXPRESSION OF TUMOR NECROSIS FACTOR ALPHA. Siberian journal of oncology. 2015;1(5):51-58. (In Russ.)
Views:
732
Email this article 
