Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8(+) T-cell function in Hodgkin lymphoma patients

Gandhi, M. K., Lambley, E., Duraiswamy, J., Dua, U., Smith, C., Elliott, S., Gill, D., Marlton, P., Seymour, J. and Khanna, R. (2006) Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8(+) T-cell function in Hodgkin lymphoma patients. Blood, 108 7: 2280-2289. doi:10.1182/blood-2006-04-015164


Author Gandhi, M. K.
Lambley, E.
Duraiswamy, J.
Dua, U.
Smith, C.
Elliott, S.
Gill, D.
Marlton, P.
Seymour, J.
Khanna, R.
Title Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8(+) T-cell function in Hodgkin lymphoma patients
Journal name Blood   Check publisher's open access policy
ISSN 0006-4971
1528-0020
Publication date 2006
Sub-type Article (original research)
DOI 10.1182/blood-2006-04-015164
Volume 108
Issue 7
Start page 2280
End page 2289
Total pages 10
Editor S. J. Shattil
Place of publication Washington, DC, United States
Publisher American Society of Hematology
Collection year 2006
Language eng
Subject C1
320206 Tumor Immunology
730108 Cancer and related disorders
Abstract In Hodgkin lymphoma (HL), the malignant Hodgkin Reed-Sternberg (HRS) cells constitute only 0.5% of 10% of the diseased tissue. The surrounding cellular infiltrate is enriched with T cells that are hypothesized to modulate antitumor immunity. We show that a marker of regulatory T cells, LAG-3, is strongly expressed on infiltrating lymphocytes present in proximity to HRS cells. Circulating regulatory T cells (CD4(+) CD25(hi) CD45 ROhi, CD4(+) CTLA4(hi), and CD4(+) LAG-3(hi)) were elevated in HL patients with active disease when compared with remission. Longitudinal profiling of EBV-specific CD8(+) T-cell responses in 94 HL patients revealed a selective loss of interferon-gamma expression by CD8(+) T cells specific for latent membrane proteins 1 and 2 (LMP1/2), irrespective of EBV tissue status. Intratumoral LAG-3 expression was associated with EBV tissue positivity, whereas FOXP3 was linked with neither LAG-3 nor EBV tissue status. The level of LAG-3 and FOXP3 expression on the tumor-infiltrating lymphocytes was coincident with impairment of LMP1/2-specific T-cell function. In vitro pre-exposure of peripheral blood mono-nuclear cells to HRS cell line supernatant significantly increased the expansion of regulatory T cells and suppressed LMP-specific T-cell responses. Deletion of CD4(+) LAG-3(+) T cells enhanced LMP-specific reactivity. These findings indicate a pivotal role for regulatory T cells and LAG-3 in the suppression of EBV-specific cell-mediated immunity in HL.
Keyword Hematology
Epstein-barr-virus
Reed-sternberg Cells
Peripheral-blood
In-vitro
Disease
Responses
Epitopes
Protein
Lines
Activation
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
2007 Higher Education Research Data Collection
School of Medicine Publications
 
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Created: Wed, 15 Aug 2007, 11:00:47 EST