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A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression
Targeting immune checkpoint pathways, such as programmed death ligand-1 (PD-L1, also known as CD274 or B7-H1) or its receptor programmed cell death-1 (PD-1) has shown improved survival for patients with numerous types of cancers, not limited to lung cancer, melanoma, renal cell carcinoma, and Hodgki...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426808/ https://www.ncbi.nlm.nih.gov/pubmed/30564891 http://dx.doi.org/10.1007/s00262-018-2282-1 |
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author | Mahoney, Kathleen M. Shukla, Sachet A. Patsoukis, Nikolaos Chaudhri, Apoorvi Browne, Edward P. Arazi, Arnon Eisenhaure, Thomas M. Pendergraft, William F. Hua, Ping Pham, Hung C. Bu, Xia Zhu, Baogong Hacohen, Nir Fritsch, Edward F. Boussiotis, Vassiliki A. Wu, Catherine J. Freeman, Gordon J. |
author_facet | Mahoney, Kathleen M. Shukla, Sachet A. Patsoukis, Nikolaos Chaudhri, Apoorvi Browne, Edward P. Arazi, Arnon Eisenhaure, Thomas M. Pendergraft, William F. Hua, Ping Pham, Hung C. Bu, Xia Zhu, Baogong Hacohen, Nir Fritsch, Edward F. Boussiotis, Vassiliki A. Wu, Catherine J. Freeman, Gordon J. |
author_sort | Mahoney, Kathleen M. |
collection | PubMed |
description | Targeting immune checkpoint pathways, such as programmed death ligand-1 (PD-L1, also known as CD274 or B7-H1) or its receptor programmed cell death-1 (PD-1) has shown improved survival for patients with numerous types of cancers, not limited to lung cancer, melanoma, renal cell carcinoma, and Hodgkin lymphoma. PD-L1 is a co-inhibitory molecule whose expression on the surface of tumor cells is associated with worse prognosis in many tumors. Here we describe a splice variant (secPD-L1) that does not splice into the transmembrane domain, but instead produces a secreted form of PD-L1 that has a unique 18 amino acid tail containing a cysteine that allows it to homodimerize and more effectively inhibit lymphocyte function than monomeric soluble PD-L1. We show that recombinant secPD-L1 can dimerize and inhibit T-cell proliferation and IFN-gamma production in vitro. The secPD-L1 variant is expressed by malignant cells in vitro that also express high levels of full-length PD-L1. Transcriptomic analysis of gene expression across The Cancer Genome Atlas found the strongest association of secPD-L1 with full-length PD-L1, but also with subsets of immunologic genes, such as in myeloid-derived suppressor cells. Moreover, the splice variant is also expressed in normal tissues and within normal peripheral blood cells it is preferentially expressed in activated myeloid cells. This is the first report of a form of secreted PD-L1 that homodimerizes and is functionally active. SecPD-L1 may function as a paracrine negative immune regulator within the tumor, since secPD-L1 does not require a cell-to-cell interaction to mediate its inhibitory effect. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00262-018-2282-1) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6426808 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-64268082019-04-05 A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression Mahoney, Kathleen M. Shukla, Sachet A. Patsoukis, Nikolaos Chaudhri, Apoorvi Browne, Edward P. Arazi, Arnon Eisenhaure, Thomas M. Pendergraft, William F. Hua, Ping Pham, Hung C. Bu, Xia Zhu, Baogong Hacohen, Nir Fritsch, Edward F. Boussiotis, Vassiliki A. Wu, Catherine J. Freeman, Gordon J. Cancer Immunol Immunother Original Article Targeting immune checkpoint pathways, such as programmed death ligand-1 (PD-L1, also known as CD274 or B7-H1) or its receptor programmed cell death-1 (PD-1) has shown improved survival for patients with numerous types of cancers, not limited to lung cancer, melanoma, renal cell carcinoma, and Hodgkin lymphoma. PD-L1 is a co-inhibitory molecule whose expression on the surface of tumor cells is associated with worse prognosis in many tumors. Here we describe a splice variant (secPD-L1) that does not splice into the transmembrane domain, but instead produces a secreted form of PD-L1 that has a unique 18 amino acid tail containing a cysteine that allows it to homodimerize and more effectively inhibit lymphocyte function than monomeric soluble PD-L1. We show that recombinant secPD-L1 can dimerize and inhibit T-cell proliferation and IFN-gamma production in vitro. The secPD-L1 variant is expressed by malignant cells in vitro that also express high levels of full-length PD-L1. Transcriptomic analysis of gene expression across The Cancer Genome Atlas found the strongest association of secPD-L1 with full-length PD-L1, but also with subsets of immunologic genes, such as in myeloid-derived suppressor cells. Moreover, the splice variant is also expressed in normal tissues and within normal peripheral blood cells it is preferentially expressed in activated myeloid cells. This is the first report of a form of secreted PD-L1 that homodimerizes and is functionally active. SecPD-L1 may function as a paracrine negative immune regulator within the tumor, since secPD-L1 does not require a cell-to-cell interaction to mediate its inhibitory effect. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00262-018-2282-1) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2018-12-18 2019 /pmc/articles/PMC6426808/ /pubmed/30564891 http://dx.doi.org/10.1007/s00262-018-2282-1 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Original Article Mahoney, Kathleen M. Shukla, Sachet A. Patsoukis, Nikolaos Chaudhri, Apoorvi Browne, Edward P. Arazi, Arnon Eisenhaure, Thomas M. Pendergraft, William F. Hua, Ping Pham, Hung C. Bu, Xia Zhu, Baogong Hacohen, Nir Fritsch, Edward F. Boussiotis, Vassiliki A. Wu, Catherine J. Freeman, Gordon J. A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression |
title | A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression |
title_full | A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression |
title_fullStr | A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression |
title_full_unstemmed | A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression |
title_short | A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression |
title_sort | secreted pd-l1 splice variant that covalently dimerizes and mediates immunosuppression |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426808/ https://www.ncbi.nlm.nih.gov/pubmed/30564891 http://dx.doi.org/10.1007/s00262-018-2282-1 |
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