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

Nguyen, Jennifer; Bernert, Richard; In, Kevin; Kang, Paul; Sebastiao, Noemi; Hu, Chengcheng; Hastings, Karen Taraszka

doi:10.1097/cmr.0000000000000230

Cited by 21 publications

(20 citation statements)

References 65 publications

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“…GILT is expressed constitutively in antigen-presenting cells and is induced by gamma-interferon in other cell types. It has an important role in HLA-II-restricted antigen processing and was reported to be expressed in most of primary and metastatic melanomas ( 54 ). Indeed, we also detected GILT in B- and T-cells and in melanoma tissues (Figure 4 A, right inset).…”

Section: Resultsmentioning

confidence: 99%

‘Hotspots’ of Antigen Presentation Revealed by Human Leukocyte Antigen Ligandomics for Neoantigen Prioritization

et al. 2017

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The remarkable clinical efficacy of the immune checkpoint blockade therapies has motivated researchers to discover immunogenic epitopes and exploit them for personalized vaccines. Human leukocyte antigen (HLA)-binding peptides derived from processing and presentation of mutated proteins are one of the leading targets for T-cell recognition of cancer cells. Currently, most studies attempt to identify neoantigens based on predicted affinity to HLA molecules, but the performance of such prediction algorithms is rather poor for rare HLA class I alleles and for HLA class II. Direct identification of neoantigens by mass spectrometry (MS) is becoming feasible; however, it is not yet applicable to most patients and lacks sensitivity. In an attempt to capitalize on existing immunopeptidomics data and extract information that could complement HLA-binding prediction, we first compiled a large HLA class I and class II immunopeptidomics database across dozens of cell types and HLA allotypes and detected hotspots that are subsequences of proteins frequently presented. About 3% of the peptidome was detected in both class I and class II. Based on the gene ontology of their source proteins and the peptide’s length, we propose that their processing may partake by the cellular class II presentation machinery. Our database captures the global nature of the in vivo peptidome averaged over many HLA alleles, and therefore, reflects the propensity of peptides to be presented on HLA complexes, which is complementary to the existing neoantigen prediction features such as binding affinity and stability or RNA abundance. We further introduce two immunopeptidomics MS-based features to guide prioritization of neoantigens: the number of peptides matching a protein in our database and the overlap of the predicted wild-type peptide with other peptides in our database. We show as a proof of concept that our immunopeptidomics MS-based features improved neoantigen prioritization by up to 50%. Overall, our work shows that, in addition to providing huge training data to improve the HLA binding prediction, immunopeptidomics also captures other aspects of the natural in vivo presentation that significantly improve prediction of clinically relevant neoantigens.

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Section: Resultsmentioning

confidence: 99%

‘Hotspots’ of Antigen Presentation Revealed by Human Leukocyte Antigen Ligandomics for Neoantigen Prioritization

et al. 2017

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“…Immunochemistry was performed using previously optimized staining protocols (7). Formalin-fixed, paraffin-embedded tissues were sectioned at 3-5 mm and mounted on charged glass slides.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Melanocytes, tumor-infiltrating APCs, and keratinocytes were identified based on morphological and histological characteristics, as described (7). For each cell type, the specimens were scored for overall staining (positive or negative), frequency, and intensity.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Subsequently, high GILT expression was found to be associated with improved survival in breast cancer (25). Our prior study identified that benign melanocytes lack GILT expression and that malignant melanocytes in 60-70% of melanoma cases express GILT (7). Heterogeneous expression in malignant melanocytes suggests that GILT expression may impact clinical outcome in melanoma.…”

mentioning

confidence: 99%

“…MHC class II is expressed on tumors derived from cells that typically express MHC class II, such as B cell lymphomas, and can be constitutively expressed and/or induced by IFN-g on other cancer cells, such as melanoma (6). Melanoma cells expressing MHC class II have been identified in one-third to the majority of melanoma tumor specimens (7)(8)(9). Melanoma cells are capable of presenting peptide Ags in the context of MHC class II (10)(11)(12)(13)(14)(15).…”

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confidence: 99%

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High GILT Expression and an Active and Intact MHC Class II Antigen Presentation Pathway Are Associated with Improved Survival in Melanoma

Buetow

Meador

Menon

et al. 2019

The Journal of Immunology

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The MHC class I Ag presentation pathway in melanoma cells has a well-established role in immune-mediated destruction of tumors. However, the clinical significance of the MHC class II Ag presentation pathway in melanoma cells is less clear. In Ag-presenting cells, IFN-γ–inducible lysosomal thiol reductase (GILT) is critical for MHC class II–restricted presentation of multiple melanoma Ags. Although not expressed in benign melanocytes of nevi, GILT and MHC class II expression is induced in malignant melanocytes in a portion of melanoma specimens. Analysis of The Cancer Genome Atlas cutaneous melanoma data set showed that high GILT mRNA expression was associated with improved overall survival. Expression of IFN-γ, TNF-α, and IL-1β was positively associated with GILT expression in melanoma specimens. These cytokines were capable of inducing GILT expression in human melanoma cells in vitro. GILT protein expression in melanocytes was induced in halo nevi, which are nevi undergoing immune-mediated regression, and is consistent with the association of GILT expression with improved survival in melanoma. To explore potential mechanisms of GILT’s association with patient outcome, we investigated pathways related to GILT function and expression. In contrast to healthy skin specimens, in which the MHC class II pathway was nearly uniformly expressed and intact, there was substantial variation in the MHC class II pathway in the The Cancer Genome Atlas melanoma specimens. Both an active and intact MHC class II pathway were associated with improved overall survival in melanoma. These studies support a role for GILT and the MHC class II Ag presentation pathway in melanoma outcome.

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Prognostic value of gamma‐interferon‐inducible lysosomal thiol reductase expression in female patients diagnosed with breast cancer

Zhou

Wang

et al. 2021

Intl Journal of Cancer

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Because of the high heterogeneity of breast cancer outcome, identification of novel prognostic biomarkers is critical to improve patient stratification and guide precise treatment. We examined the prognostic value of gamma‐interferon‐inducible lysosomal thiol reductase (GILT) expression in a training set of 416 breast cancer patients and a validation set of 210 patients, and performed functional studies to investigate the functions and underlying mechanisms of GILT on breast cancer prognosis. Our results indicated that high GILT expression in breast cancer cells was associated with improved disease‐free survival (DFS; hazard ratio [HR] = 0.189, 95% confidence interval [CI]: 0.099‐0.361) and breast cancer‐specific survival (BCSS; HR = 0.187, 95% CI: 0.080‐0.437) of breast cancer patients both in the training set and the external validation set (HR = 0.453, 95% CI: 0.235‐0.873 for DFS, HR = 0.488, 95% CI: 0.245‐0.970 for BCSS). In vitro and in vivo studies showed that GILT overexpression inhibited breast cancer cells proliferation, invasion, migration and tumor formation in nude mice and increased sensitivity of breast cancer cells to standard treatment. Proteomics analysis indicated that GILT inhibited reactive oxygen species (ROS) and autophagy activation in breast cancer cells, and GILT overexpression‐mediated tumor growth was further enhanced in the presence of autophagy or ROS inhibitors. Our results demonstrate that GILT expression can be effectively used to predict the prognosis and guide treatment strategies of breast cancer patients.

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

Cited by 21 publications

References 65 publications

‘Hotspots’ of Antigen Presentation Revealed by Human Leukocyte Antigen Ligandomics for Neoantigen Prioritization

‘Hotspots’ of Antigen Presentation Revealed by Human Leukocyte Antigen Ligandomics for Neoantigen Prioritization

High GILT Expression and an Active and Intact MHC Class II Antigen Presentation Pathway Are Associated with Improved Survival in Melanoma

Prognostic value of gamma‐interferon‐inducible lysosomal thiol reductase expression in female patients diagnosed with breast cancer

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