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Gamma-IFN-inducible-lysosomal thiol reductase modulates acidic proteases and HLA class II antigen processing in melanoma

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Abstract

HLA class II-restricted antigen (Ag) processing and presentation are important for the activation of CD4+ T cells, which are the central orchestrating cells of immune responses. The majority of melanoma cells either expresses, or can be induced to express, HLA class II proteins. Thus, they are prime targets for immune mediated elimination by class II-restricted CD4+ T cells. We have previously shown that human melanoma cells lack an important enzyme, gamma interferon-inducible lysosomal thiol-reductase (GILT), capable of perturbing immune recognition of these tumors. Here, we show that GILT expression in human melanoma cells enhances Ag processing and presentation via HLA class II molecules. We also show that GILT expression influences the generation of active forms of cysteinyl proteases, cathepsins B, L and S, as well as an aspartyl protease cathepsin D in melanoma cells. Mechanistic studies revealed that GILT does not regulate acidic cathepsins at the transcriptional level; rather it colocalizes with the cathepsins and influences HLA class II Ag processing. GILT expression in melanoma cells also elevated HLA-DM molecules, which favor epitope loading onto class II in the endolysosomal compartments, enhancing CD4+ T cell recognition. These data suggest that GILT-expressing melanoma cells could prove to be very promising for direct antigen presentation and CD4+ T cell recognition, and may have direct implications for the design of cancer vaccines.

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Acknowledgments

We are grateful to Dr. Janice Blum (Indiana University, Indianapolis) for providing us with cell lines, antibodies and reagents. We also thank Dr. P. Cresswell (Yale University) and Patrick W. O’Donnell (Indiana University) for GILT-expressing melanoma cells. This work was supported by grants from the Leukemia and Lymphoma Society (No. 3024), ACS-IRG (No. 85241), Hollings Cancer Center Seed Grant (GC-3319-05-4498CM) to A.H., and the NIH grant DE12603 (S.V.R).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, BSB-201, Charleston, SC, 29425, USA

    Oliver G. Goldstein, Laela M. Hajiaghamohseni, Shereen Amria & Azizul Haque

  2. Hollings Cancer Center, Medical University of South Carolina, 173 Ashley Avenue, BSB-201, Charleston, SC, 29425, USA

    Oliver G. Goldstein, Laela M. Hajiaghamohseni, Shereen Amria & Azizul Haque

  3. Children’s Research Institute, Medical University of South Carolina, 173 Ashley Avenue, BSB-201, Charleston, SC, 29425, USA

    Oliver G. Goldstein, Shereen Amria, Kumaran Sundaram, Sakamuri V. Reddy & Azizul Haque

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  1. Oliver G. Goldstein
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Correspondence to Azizul Haque.

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262_2008_483_MOESM1_ESM.tif

Supplementary Fig. 1 GILT expression did not alter cathepsins mRNA levels in melanoma cells. RNA isolated from melanoma cells 1359-mel and 1359-mel.GILT were analyzed by real time RT-PCR for cathepsins B, D, L and S mRNA. Relative levels of Cat mRNA expression were normalized in all the samples analyzed with respect to the levels of GAPDH amplification. Cat B, D, L and S mRNA expression levels were presented as fold increase over control. (TIF 98 kb)

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Goldstein, O.G., Hajiaghamohseni, L.M., Amria, S. et al. Gamma-IFN-inducible-lysosomal thiol reductase modulates acidic proteases and HLA class II antigen processing in melanoma. Cancer Immunol Immunother 57, 1461–1470 (2008). https://doi.org/10.1007/s00262-008-0483-8

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