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Mechanisms and Effects of Loss of Human Leukocyte Antigen Class II Expression in Immune-Privileged Site-Associated B-Cell Lymphoma

Authors' Affiliations: Departments of ¹ Pathology and Laboratory Medicine and ² Clinical Genetics, University Medical Center Groningen, Groningen, the Netherlands; ³ Department of Bioinformatics, Agendia B.V.; ⁴ Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands; ⁵ Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands; and ⁶ Department of Pathology, University of Wuerzburg, Wuerzburg, Germany

Requests for reprints: Marije Booman, Department of Pathology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands. Phone: 31-50-3611284; Fax: 31-50-3632510; E-mail: m.booman{at}path.umcg.nl.

Purpose and Experimental Design: Loss of human leukocyte antigen (HLA) expression on tumor cells is frequent in diffuse large B-cell lymphoma (DLBCL) arising in immune-privileged sites, such as the testis and central nervous system, and is associated with small homozygous deletions of HLA-DQ/HLA-DR and larger hemizygous deletions of the MHC region. To better understand the significance of down-regulation of HLA class II expression in relation to the homozygous and hemizygous deletions, we analyzed global gene expression patterns in a series of 26 testicular DLBCL after characterization of these deletions.

Results: Low levels of HLA-DR mRNA in whole testicular DLBCL samples were associated with a strong down-regulation of numerous immune-related genes specific for T cells, macrophages, antigen presentation and processing, lymphocyte activation, chemokines and chemokine receptors, and the complement system. The number of CD3⁺ tumor-infiltrating T cells was also significantly lower in low expressors of HLA-DR mRNA. Interestingly, hemizygous and homozygous deletions in the MHC region did not have any additional effect on global gene expression.

Conclusion: In conclusion, we found that loss of HLA class II mRNA expression in testicular DLBCL is associated with a significant change in global gene expression patterns. This effect is independent of the mechanism causing the down-regulation of HLA class II genes in the lymphoma cells.

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