Low GILT Expression is Associated with Poor Patient Survival in Diffuse Large B-Cell Lymphoma

Abstract

The major histocompatibility complex (MHC) class II-restricted antigen processing pathway presents antigenic peptides acquired in the endocytic route for the activation of CD4+ T cells. Multiple cancers express MHC class II, which may influence the anti-tumor immune response and patient outcome. Low MHC class II expression is associated with poor survival in diffuse large B-cell lymphoma (DLBCL), the most common form of aggressive non-Hodgkin lymphoma. Therefore, we investigated whether gamma-interferon-inducible lysosomal thiol reductase (GILT), an upstream component of the MHC class II-restricted antigen processing pathway that is not regulated by the transcription factor class II transactivator, may be important in DLBCL biology. GILT reduces protein disulfide bonds in the endocytic compartment, exposing additional epitopes for binding to MHC class II and facilitating antigen presentation. In each of four independent gene expression profiling cohorts with a total of 585 DLBCL patients, low GILT expression was significantly associated with poor overall survival. In contrast, low expression of a classical MHC class II gene, HLA-DRA, was associated with poor survival in one of four cohorts. The association of low GILT expression with poor survival was independent of established clinical and molecular prognostic factors, the International Prognostic Index and the cell of origin classification, respectively. Immunohistochemical analysis of GILT expression in 96 DLBCL cases demonstrated variation in GILT protein expression within tumor cells which correlated strongly with GILT mRNA expression. These studies identify a novel association between GILT expression and clinical outcome in lymphoma. Our findings underscore the role of antigen processing in DLBCL and suggest that molecules targeting this pathway warrant investigation as potential therapeutics.

Gamma-interferon-inducible lysosomal thiol reductase is upregulated in human melanoma

“…Previously optimized staining protocols for GILT and MHC class II [5] were modified to use a red chromagen in order to avoid confusion of melanin pigment with a brown chromagen. Formalin-fixed, paraffin-embedded tissues were sectioned at 3-5 μm and mounted on charged glass slides.…”

“…GILT serves a unique function of reducing protein disulfide bonds in the endocytic compartment, as GILT is the only reductase known to reside in this compartment. Previously, GILT has been shown to be constitutively expressed in professional antigen presenting cells (APCs), including B cells, monocytes/macrophages and bone marrow-derived dendritic cells [3-5]. GILT expression can be induced in other cell types such as melanoma cell lines by interferon (IFN)-γ [6].…”

HLA class II antigen-processing pathway in tumors: Molecular defects and clinical relevance

“…This caused immune tolerance or unresponsiveness to leukemia antigens and lead to a significantly shortened disease-free survival of patients with AML or diffuse large B-cell lymphoma. 23,65,66 In contrast, some CLIP ¡ tumor cells were able to process li-independent endogeneous antigens generated by the proteasome for HLA class II-restricted presentation thereby activating TAA-specific CD4 C T cells. 23,67 Furthermore, it has recently been suggested that the different HLA class II phenotypes in tumors can be controlled at the post-transcriptional level, in particular by microRNAs (miRs).…”

Improved Innate Immune Responses by Frondanol A5, a Sea Cucumber Extract, Prevent Intestinal Tumorigenesis

“…Levels of GILT expression are often associated with poor patient survival, indicating an impaired presentation of class-II-restricted peptides (47). Further, lower GILT expression reduced CD4 + T cell-mediated responses in in vivo mouse models (48 – 50).…”