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Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes
SIMPLE SUMMARY: Triple-negative breast cancer (TNBC) is an aggressive disease that responds in a limited manner to immune checkpoint blockades targeting the PD-L1/PD-1 axis, suggesting that PD-L1 potentiates TNBC progression via pathways not related to immune suppression. We demonstrated that, in hu...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870053/ https://www.ncbi.nlm.nih.gov/pubmed/35205789 http://dx.doi.org/10.3390/cancers14041042 |
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author | Erlichman, Nofar Baram, Tamir Meshel, Tsipi Morein, Dina Da’adoosh, Benny Ben-Baruch, Adit |
author_facet | Erlichman, Nofar Baram, Tamir Meshel, Tsipi Morein, Dina Da’adoosh, Benny Ben-Baruch, Adit |
author_sort | Erlichman, Nofar |
collection | PubMed |
description | SIMPLE SUMMARY: Triple-negative breast cancer (TNBC) is an aggressive disease that responds in a limited manner to immune checkpoint blockades targeting the PD-L1/PD-1 axis, suggesting that PD-L1 potentiates TNBC progression via pathways not related to immune suppression. We demonstrated that, in human breast cancer cells, PD-L1 expression increased in a cell-autonomous manner tumor cell growth, invasion and release of pro-metastatic factors; these activities were elevated by exposure to PD-1 and were markedly impaired in S283-mutated PD-L1-expressing cells. Invasion of WT-PD-L1-expressing TNBC cells depended on autocrine chemokine circuits, involving CXCR1/2, CCR2, CCR5 and their ligands. In T cell-deficient mice, WT-PD-L1 exhibited increased tumor growth and metastasis by TNBC cells, whereas S283A-PD-L1-expressing cells showed a very poor tumorigenic and metastatic profile. These findings on cell-autonomous and PD-1-induced pro-metastatic activities of PD-L1 in cancer cells suggest that treatments targeting PD-L1 could improve the efficacy of immune-targeting checkpoint inhibitors, e.g., anti-PD-1 or anti-CTLA-4 in TNBC. ABSTRACT: Therapies targeting the PD-L1/PD-1 axis have recently been introduced to triple-negative breast cancer (TNBC) with limited efficacy, suggesting that this axis promotes tumor progression through mechanisms other than immune suppression. Here, we over-expressed WT-PD-L1 in human TNBC cells (express endogenous PD-L1) and in luminal-A breast cancer cells (no endogenous PD-L1 expression) and demonstrated that cell-autonomous PD-L1 activities lead to increased tumor cell growth, invasion and release of pro-metastatic factors (CXCL8, sICAM-1, GM-CSF). These activities were promoted by PD-1 and were inhibited by mutating S283 in PD-L1. Invasion of WT-PD-L1-cells required signaling by chemokine receptors CXCR1/2, CCR2 and CCR5 through autocrine circuits involving CXCL8, CCL2 and CCL5. Studies with T cell-deficient mice demonstrated that cell-autonomous WT-PD-L1 activities in TNBC cells increased tumor growth and metastasis compared to knock-out (KO)-PD-L1-cells, whereas S283A-PD-L1-expressing cells had minimal ability to form tumors and did not metastasize. Overall, our findings reveal autonomous and PD-1-induced tumor-promoting activities of PD-L1 that depend on S283 and on chemokine circuits. These results suggest that TNBC patients whose tumors express PD-L1 could benefit from therapies that prevent immune suppression by targeting PD-1/CTLA-4, alongside with antibodies to PD-L1, which would allow maximal impact by mainly targeting the cancer cells. |
format | Online Article Text |
id | pubmed-8870053 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-88700532022-02-25 Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes Erlichman, Nofar Baram, Tamir Meshel, Tsipi Morein, Dina Da’adoosh, Benny Ben-Baruch, Adit Cancers (Basel) Article SIMPLE SUMMARY: Triple-negative breast cancer (TNBC) is an aggressive disease that responds in a limited manner to immune checkpoint blockades targeting the PD-L1/PD-1 axis, suggesting that PD-L1 potentiates TNBC progression via pathways not related to immune suppression. We demonstrated that, in human breast cancer cells, PD-L1 expression increased in a cell-autonomous manner tumor cell growth, invasion and release of pro-metastatic factors; these activities were elevated by exposure to PD-1 and were markedly impaired in S283-mutated PD-L1-expressing cells. Invasion of WT-PD-L1-expressing TNBC cells depended on autocrine chemokine circuits, involving CXCR1/2, CCR2, CCR5 and their ligands. In T cell-deficient mice, WT-PD-L1 exhibited increased tumor growth and metastasis by TNBC cells, whereas S283A-PD-L1-expressing cells showed a very poor tumorigenic and metastatic profile. These findings on cell-autonomous and PD-1-induced pro-metastatic activities of PD-L1 in cancer cells suggest that treatments targeting PD-L1 could improve the efficacy of immune-targeting checkpoint inhibitors, e.g., anti-PD-1 or anti-CTLA-4 in TNBC. ABSTRACT: Therapies targeting the PD-L1/PD-1 axis have recently been introduced to triple-negative breast cancer (TNBC) with limited efficacy, suggesting that this axis promotes tumor progression through mechanisms other than immune suppression. Here, we over-expressed WT-PD-L1 in human TNBC cells (express endogenous PD-L1) and in luminal-A breast cancer cells (no endogenous PD-L1 expression) and demonstrated that cell-autonomous PD-L1 activities lead to increased tumor cell growth, invasion and release of pro-metastatic factors (CXCL8, sICAM-1, GM-CSF). These activities were promoted by PD-1 and were inhibited by mutating S283 in PD-L1. Invasion of WT-PD-L1-cells required signaling by chemokine receptors CXCR1/2, CCR2 and CCR5 through autocrine circuits involving CXCL8, CCL2 and CCL5. Studies with T cell-deficient mice demonstrated that cell-autonomous WT-PD-L1 activities in TNBC cells increased tumor growth and metastasis compared to knock-out (KO)-PD-L1-cells, whereas S283A-PD-L1-expressing cells had minimal ability to form tumors and did not metastasize. Overall, our findings reveal autonomous and PD-1-induced tumor-promoting activities of PD-L1 that depend on S283 and on chemokine circuits. These results suggest that TNBC patients whose tumors express PD-L1 could benefit from therapies that prevent immune suppression by targeting PD-1/CTLA-4, alongside with antibodies to PD-L1, which would allow maximal impact by mainly targeting the cancer cells. MDPI 2022-02-18 /pmc/articles/PMC8870053/ /pubmed/35205789 http://dx.doi.org/10.3390/cancers14041042 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Erlichman, Nofar Baram, Tamir Meshel, Tsipi Morein, Dina Da’adoosh, Benny Ben-Baruch, Adit Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes |
title | Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes |
title_full | Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes |
title_fullStr | Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes |
title_full_unstemmed | Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes |
title_short | Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes |
title_sort | tumor cell-autonomous pro-metastatic activities of pd-l1 in human breast cancer are mediated by pd-l1-s283 and chemokine axes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870053/ https://www.ncbi.nlm.nih.gov/pubmed/35205789 http://dx.doi.org/10.3390/cancers14041042 |
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