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Correlation of the tumor escape phenotype with loss of PRELP expression in melanoma

BACKGROUND: Despite immunotherapies having revolutionized the treatment of advanced cutaneous melanoma, effective and durable responses were only reported in a few patients. A better understanding of the interaction of melanoma cells with the microenvironment, including extracellular matrix (ECM) co...

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Autores principales: Schäfer, Helene, Subbarayan, Karthikeyan, Massa, Chiara, Vaxevanis, Christoforos, Mueller, Anja, Seliger, Barbara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10512569/
https://www.ncbi.nlm.nih.gov/pubmed/37730606
http://dx.doi.org/10.1186/s12967-023-04476-x
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author Schäfer, Helene
Subbarayan, Karthikeyan
Massa, Chiara
Vaxevanis, Christoforos
Mueller, Anja
Seliger, Barbara
author_facet Schäfer, Helene
Subbarayan, Karthikeyan
Massa, Chiara
Vaxevanis, Christoforos
Mueller, Anja
Seliger, Barbara
author_sort Schäfer, Helene
collection PubMed
description BACKGROUND: Despite immunotherapies having revolutionized the treatment of advanced cutaneous melanoma, effective and durable responses were only reported in a few patients. A better understanding of the interaction of melanoma cells with the microenvironment, including extracellular matrix (ECM) components, might provide novel therapeutic options. Although the ECM has been linked to several hallmarks of cancer, little information is available regarding the expression and function of the ECM protein purine-arginine-rich and leucine-rich protein (PRELP) in cancer, including melanoma. METHODS: The structural integrity, expression and function of PRELP, its correlation with the expression of immune modulatory molecules, immune cell infiltration and clinical parameters were determined using standard methods and/or bioinformatics. RESULTS: Bioinformatics analysis revealed a heterogeneous, but statistically significant reduced PRELP expression in available datasets of skin cutaneous melanoma when compared to adjacent normal tissues, which was associated with reduced patients’ survival, low expression levels of components of the MHC class I antigen processing machinery (APM) and interferon (IFN)-γ signal transduction pathway, but increased expression of the transforming growth factor (TGF)-β isoform 1 (TFGB1) and TGF-β receptor 1 (TGFBR1). In addition, a high frequency of intra-tumoral T cells directly correlated with the expression of MHC class I and PRELP as well as the T cell attractant CCL5 in melanoma lesions. Marginal to low PRELP expression levels were found in the 47/49 human melanoma cell lines analysis. Transfection of PRELP into melanoma cell lines restored MHC class I surface expression due to transcriptional upregulation of major MHC class I APM and IFN-γ pathway components. In addition, PRELP overexpression is accompanied by high CCL5 secretion levels in cell supernatant, an impaired TGF-β signaling as well as a reduced cell proliferation, migration and invasion of melanoma cells. CONCLUSIONS: Our findings suggest that PRELP induces the expression of MHC class I and CCL5 in melanoma, which might be involved in an enhanced T cell recruitment and immunogenicity associated with an improved patients’ outcome. Therefore, PRELP might serve as a marker for predicting disease progression and its recovery could revert the tumorigenic phenotype, which represents a novel therapeutic option for melanoma. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04476-x.
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spelling pubmed-105125692023-09-22 Correlation of the tumor escape phenotype with loss of PRELP expression in melanoma Schäfer, Helene Subbarayan, Karthikeyan Massa, Chiara Vaxevanis, Christoforos Mueller, Anja Seliger, Barbara J Transl Med Research BACKGROUND: Despite immunotherapies having revolutionized the treatment of advanced cutaneous melanoma, effective and durable responses were only reported in a few patients. A better understanding of the interaction of melanoma cells with the microenvironment, including extracellular matrix (ECM) components, might provide novel therapeutic options. Although the ECM has been linked to several hallmarks of cancer, little information is available regarding the expression and function of the ECM protein purine-arginine-rich and leucine-rich protein (PRELP) in cancer, including melanoma. METHODS: The structural integrity, expression and function of PRELP, its correlation with the expression of immune modulatory molecules, immune cell infiltration and clinical parameters were determined using standard methods and/or bioinformatics. RESULTS: Bioinformatics analysis revealed a heterogeneous, but statistically significant reduced PRELP expression in available datasets of skin cutaneous melanoma when compared to adjacent normal tissues, which was associated with reduced patients’ survival, low expression levels of components of the MHC class I antigen processing machinery (APM) and interferon (IFN)-γ signal transduction pathway, but increased expression of the transforming growth factor (TGF)-β isoform 1 (TFGB1) and TGF-β receptor 1 (TGFBR1). In addition, a high frequency of intra-tumoral T cells directly correlated with the expression of MHC class I and PRELP as well as the T cell attractant CCL5 in melanoma lesions. Marginal to low PRELP expression levels were found in the 47/49 human melanoma cell lines analysis. Transfection of PRELP into melanoma cell lines restored MHC class I surface expression due to transcriptional upregulation of major MHC class I APM and IFN-γ pathway components. In addition, PRELP overexpression is accompanied by high CCL5 secretion levels in cell supernatant, an impaired TGF-β signaling as well as a reduced cell proliferation, migration and invasion of melanoma cells. CONCLUSIONS: Our findings suggest that PRELP induces the expression of MHC class I and CCL5 in melanoma, which might be involved in an enhanced T cell recruitment and immunogenicity associated with an improved patients’ outcome. Therefore, PRELP might serve as a marker for predicting disease progression and its recovery could revert the tumorigenic phenotype, which represents a novel therapeutic option for melanoma. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04476-x. BioMed Central 2023-09-20 /pmc/articles/PMC10512569/ /pubmed/37730606 http://dx.doi.org/10.1186/s12967-023-04476-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Schäfer, Helene
Subbarayan, Karthikeyan
Massa, Chiara
Vaxevanis, Christoforos
Mueller, Anja
Seliger, Barbara
Correlation of the tumor escape phenotype with loss of PRELP expression in melanoma
title Correlation of the tumor escape phenotype with loss of PRELP expression in melanoma
title_full Correlation of the tumor escape phenotype with loss of PRELP expression in melanoma
title_fullStr Correlation of the tumor escape phenotype with loss of PRELP expression in melanoma
title_full_unstemmed Correlation of the tumor escape phenotype with loss of PRELP expression in melanoma
title_short Correlation of the tumor escape phenotype with loss of PRELP expression in melanoma
title_sort correlation of the tumor escape phenotype with loss of prelp expression in melanoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10512569/
https://www.ncbi.nlm.nih.gov/pubmed/37730606
http://dx.doi.org/10.1186/s12967-023-04476-x
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