Immune Checkpoint Profiling in Humanized Breast Cancer Mice Revealed Cell-Specific LAG-3/PD-1/TIM-3 Co-Expression and Elevated PD-1/TIM-3 Secretion
Checkpoint blockade is particularly based on PD-1/PD-L1-inhibiting antibodies. However, an efficient immunological tumor defense can be blocked not only by PD-(L)1 but also by the presence of additional immune checkpoint molecules. Here, we investigated the co-expression of several immune checkpoint...
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MDPI AG
2023-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/9/2615 |
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| author | Christina Bruss Kerstin Kellner Veruschka Albert James A. Hutchinson Stephan Seitz Olaf Ortmann Gero Brockhoff Anja K. Wege |
| author_facet | Christina Bruss Kerstin Kellner Veruschka Albert James A. Hutchinson Stephan Seitz Olaf Ortmann Gero Brockhoff Anja K. Wege |
| author_sort | Christina Bruss |
| collection | DOAJ |
| description | Checkpoint blockade is particularly based on PD-1/PD-L1-inhibiting antibodies. However, an efficient immunological tumor defense can be blocked not only by PD-(L)1 but also by the presence of additional immune checkpoint molecules. Here, we investigated the co-expression of several immune checkpoint proteins and the soluble forms thereof (e.g., PD-1, TIM-3, LAG-3, PD-L1, PD-L2 and others) in humanized tumor mice (HTM) simultaneously harboring cell line-derived (JIMT-1, MDA-MB-231, MCF-7) or patient-derived breast cancer and a functional human immune system. We identified tumor-infiltrating T cells with a triple-positive PD-1, LAG-3 and TIM-3 phenotype. While PD-1 expression was increased in both the CD4 and CD8 T cells, TIM-3 was found to be upregulated particularly in the cytotoxic T cells in the MDA-MB-231-based HTM model. High levels of soluble TIM-3 and galectin-9 (a TIM-3 ligand) were detected in the serum. Surprisingly, soluble PD-L2, but only low levels of sPD-L1, were found in mice harboring PD-L1-positive tumors. Analysis of a dataset containing 3039 primary breast cancer samples on the R2 Genomics Analysis Platform revealed increased TIM-3, galectin-9 and LAG-3 expression, not only in triple-negative breast cancer but also in the HER2<sup>+</sup> and hormone receptor-positive breast cancer subtypes. These data indicate that LAG-3 and TIM-3 represent additional key molecules within the breast cancer anti-immunity landscape. |
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| format | Article |
| id | doaj.art-7e61771962f04ba7bf3d6acf5e18cb96 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T04:22:20Z |
| publishDate | 2023-05-01 |
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| record_format | Article |
| series | Cancers |
| spelling | doaj.art-7e61771962f04ba7bf3d6acf5e18cb962023-11-17T22:42:11ZengMDPI AGCancers2072-66942023-05-01159261510.3390/cancers15092615Immune Checkpoint Profiling in Humanized Breast Cancer Mice Revealed Cell-Specific LAG-3/PD-1/TIM-3 Co-Expression and Elevated PD-1/TIM-3 SecretionChristina Bruss0Kerstin Kellner1Veruschka Albert2James A. Hutchinson3Stephan Seitz4Olaf Ortmann5Gero Brockhoff6Anja K. Wege7Department of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, GermanyDepartment of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, GermanyDepartment of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, GermanyDepartment of Surgery, University Hospital Regensburg, 93053 Regensburg, GermanyDepartment of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, GermanyDepartment of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, GermanyDepartment of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, GermanyDepartment of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, GermanyCheckpoint blockade is particularly based on PD-1/PD-L1-inhibiting antibodies. However, an efficient immunological tumor defense can be blocked not only by PD-(L)1 but also by the presence of additional immune checkpoint molecules. Here, we investigated the co-expression of several immune checkpoint proteins and the soluble forms thereof (e.g., PD-1, TIM-3, LAG-3, PD-L1, PD-L2 and others) in humanized tumor mice (HTM) simultaneously harboring cell line-derived (JIMT-1, MDA-MB-231, MCF-7) or patient-derived breast cancer and a functional human immune system. We identified tumor-infiltrating T cells with a triple-positive PD-1, LAG-3 and TIM-3 phenotype. While PD-1 expression was increased in both the CD4 and CD8 T cells, TIM-3 was found to be upregulated particularly in the cytotoxic T cells in the MDA-MB-231-based HTM model. High levels of soluble TIM-3 and galectin-9 (a TIM-3 ligand) were detected in the serum. Surprisingly, soluble PD-L2, but only low levels of sPD-L1, were found in mice harboring PD-L1-positive tumors. Analysis of a dataset containing 3039 primary breast cancer samples on the R2 Genomics Analysis Platform revealed increased TIM-3, galectin-9 and LAG-3 expression, not only in triple-negative breast cancer but also in the HER2<sup>+</sup> and hormone receptor-positive breast cancer subtypes. These data indicate that LAG-3 and TIM-3 represent additional key molecules within the breast cancer anti-immunity landscape.https://www.mdpi.com/2072-6694/15/9/2615humanized tumor mice (HTM)breast cancerhematopoietic stem cells (HSC)TIM-3LAG-3galectin-9 |
| spellingShingle | Christina Bruss Kerstin Kellner Veruschka Albert James A. Hutchinson Stephan Seitz Olaf Ortmann Gero Brockhoff Anja K. Wege Immune Checkpoint Profiling in Humanized Breast Cancer Mice Revealed Cell-Specific LAG-3/PD-1/TIM-3 Co-Expression and Elevated PD-1/TIM-3 Secretion Cancers humanized tumor mice (HTM) breast cancer hematopoietic stem cells (HSC) TIM-3 LAG-3 galectin-9 |
| title | Immune Checkpoint Profiling in Humanized Breast Cancer Mice Revealed Cell-Specific LAG-3/PD-1/TIM-3 Co-Expression and Elevated PD-1/TIM-3 Secretion |
| title_full | Immune Checkpoint Profiling in Humanized Breast Cancer Mice Revealed Cell-Specific LAG-3/PD-1/TIM-3 Co-Expression and Elevated PD-1/TIM-3 Secretion |
| title_fullStr | Immune Checkpoint Profiling in Humanized Breast Cancer Mice Revealed Cell-Specific LAG-3/PD-1/TIM-3 Co-Expression and Elevated PD-1/TIM-3 Secretion |
| title_full_unstemmed | Immune Checkpoint Profiling in Humanized Breast Cancer Mice Revealed Cell-Specific LAG-3/PD-1/TIM-3 Co-Expression and Elevated PD-1/TIM-3 Secretion |
| title_short | Immune Checkpoint Profiling in Humanized Breast Cancer Mice Revealed Cell-Specific LAG-3/PD-1/TIM-3 Co-Expression and Elevated PD-1/TIM-3 Secretion |
| title_sort | immune checkpoint profiling in humanized breast cancer mice revealed cell specific lag 3 pd 1 tim 3 co expression and elevated pd 1 tim 3 secretion |
| topic | humanized tumor mice (HTM) breast cancer hematopoietic stem cells (HSC) TIM-3 LAG-3 galectin-9 |
| url | https://www.mdpi.com/2072-6694/15/9/2615 |
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