Document Detail


Lymphomas are sensitive to perforin-dependent cytotoxic pathways despite expression of PI-9 and overexpression of bcl-2.
MedLine Citation:
PMID:  16373664     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
There is considerable interest in immunotherapeutic approaches for lymphoma. The expression of proteinase inhibitor 9 (PI-9), a molecule that inactivates granzyme B, is considered an immune escape mechanism in lymphoma. Further, lymphomas frequently overexpress the antiapoptotic molecule bcl-2, which is able to inhibit perforin-dependent cytotoxic pathways. In this study, the impact of PI-9 and bcl-2 expression on the sensitivity of lymphomas to T- and natural killer (NK) cell-mediated cytotoxicity was analyzed. We found PI-9 expression in 10 of 18 lymphoma cell lines and in 9 of 14 primary lymphomas. Overexpression of bcl-2 was found in 8 of 18 cell lines and in 12 of 14 primary lymphomas. All lymphoma cells were sensitive to cytolysis by specific T cells and cytokine-activated NK cells, and no difference in sensitivity was observed with respect to PI-9 or bcl-2 expression. Cytolysis was mediated predominantly through perforin-dependent pathways despite expression of PI-9 and bcl-2. Interestingly, the majority of lymphoma cells were resistant to cytolysis by resting allogeneic NK cells. This was due to the failure of lymphomas to induce degranulation of resting NK cells. These results show that resistance to perforin-dependent pathways is not a relevant immune escape mechanism in lymphoma and therefore is unlikely to impair clinical outcome of immunotherapeutic approaches.
Authors:
Robert Godal; Ulrich Keilholz; Lutz Uharek; Anne Letsch; Anne Marie Asemissen; Antonia Busse; Il-Kang Na; Eckhard Thiel; Carmen Scheibenbogen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-12-22
Journal Detail:
Title:  Blood     Volume:  107     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  2006 Apr 
Date Detail:
Created Date:  2006-04-06     Completed Date:  2006-05-22     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3205-11     Citation Subset:  AIM; IM    
Affiliation:
Department of Internal Medicine, St Elizabeth Oncological Institute, Bratislava, Slovakia.
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MeSH Terms
Descriptor/Qualifier:
Cytokines / immunology
Female
Gene Expression Regulation, Leukemic / immunology*
HL-60 Cells
Humans
Immunotherapy / methods
Jurkat Cells
K562 Cells
Killer Cells, Natural / immunology*
Lymphocyte Activation / genetics,  immunology
Lymphoma / genetics,  immunology*,  therapy
Male
Membrane Glycoproteins / immunology
Perforin
Pore Forming Cytotoxic Proteins
Proto-Oncogene Proteins c-bcl-2 / genetics,  immunology*
Serpins / genetics,  immunology*
T-Lymphocytes, Cytotoxic / immunology
Tumor Escape / immunology*
Chemical
Reg. No./Substance:
0/Cytokines; 0/Membrane Glycoproteins; 0/Pore Forming Cytotoxic Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/SERPINB9 protein, human; 0/Serpins; 126465-35-8/Perforin
Comments/Corrections
Comment In:
Blood. 2006 Jun 15;107(12):4974-5; author reply 4975   [PMID:  16754780 ]

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