CD8+ T Lymphocytes Immune Depletion and LAG-3 Overexpression in Hodgkin Lymphoma Tumor Microenvironment Exposed to Anti-PD-1 Immunotherapy
<i>Background</i>: Resistance to anti-PD-1 remains a considerable clinical challenge for the treatment of patients with classical Hodgkin lymphoma (cHL), and mechanisms of anti-PD-1 resistance remain unknown. This pilot study aims to investigate the tumor microenvironment in patients wit...
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2021
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oai:doaj.org-article:da9c5b5b2f4d417bba91f68888616b652021-11-11T15:33:41ZCD8+ T Lymphocytes Immune Depletion and LAG-3 Overexpression in Hodgkin Lymphoma Tumor Microenvironment Exposed to Anti-PD-1 Immunotherapy10.3390/cancers132154872072-6694https://doaj.org/article/da9c5b5b2f4d417bba91f68888616b652021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5487https://doaj.org/toc/2072-6694<i>Background</i>: Resistance to anti-PD-1 remains a considerable clinical challenge for the treatment of patients with classical Hodgkin lymphoma (cHL), and mechanisms of anti-PD-1 resistance remain unknown. This pilot study aims to investigate the tumor microenvironment in patients with cHL relapsing after anti-PD-1. <i>Methods</i>: This study investigated tumor samples of eight patients with cHL, including four patients exposed to anti-PD-1 with a paired longitudinal histological analysis before and after anti-PD-1, and four patients not exposed to anti-PD-1 who served as control for the cellular biological investigations. Fresh cells tumor microenvironment analysis included phenotypic characterization of their T cell surfaces immune checkpoint markers PD-1, PD-L1, ICOS, TIM-3, LAG-3, 41-BB and BTLA. Tumor tissues immunohistochemistry staining included CD30, CD4, CD8, CD68, CD163, PD-L1, PD-1, LAG-3 and TIM-3. <i>Findings</i>: Paired longitudinal tumor tissues analysis in the tumor microenvironment found a CD8+ lymphocytes tumor depletion and an increase of LAG-3 staining after anti-PD-1 exposure. The fresh cells analysis of the tumor microenvironment in patients exposed to anti-PD-1 found CD8+ lymphocyte depletion, with an elevated CD4+/CD8+ lymphocytes ratio (median ratio 9.77 in exposed anti-PD-1 versus 2.39 in not-exposed anti-PD-1 patients; <i>p</i> = 0.0943). On the cell surfaces of CD4+ lymphocytes, the median positive expression of LAG-3 was significantly higher in the samples exposed to anti-PD-1 compared to the controls (15.05 [IQR:17.91–10.65] versus 3.84 [IQR 1.87–6.57]; <i>p</i> = 0.0376). <i>Interpretation</i>: This pilot study proposes hypotheses for understanding the resistance to immunotherapies in patients with Hodgkin lymphoma. Hodgkin lymphoma exposed to anti-PD-1 correlated in tumor microenvironment with an immune depletion of CD8+ T lymphocytes and overexpression of LAG-3 on CD4+ helper T lymphocytes.Jean-Marie MichotSeverine MouraudJulien AdamJulien LazaroviciCamille BigenwaldCharlotte RigaudLambros TselikasPeggy DartiguesAlina DanuAmélie BigorgneVeronique MinardDavid GhezAurélien MarabelleLaurence ZitvogelVincent RibragMDPI AGarticleHodgkin lymphomaimmune checkpoint inhibitorsLAG-3anti-PD-1Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5487, p 5487 (2021) |
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DOAJ |
| collection |
DOAJ |
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EN |
| topic |
Hodgkin lymphoma immune checkpoint inhibitors LAG-3 anti-PD-1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
| spellingShingle |
Hodgkin lymphoma immune checkpoint inhibitors LAG-3 anti-PD-1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Jean-Marie Michot Severine Mouraud Julien Adam Julien Lazarovici Camille Bigenwald Charlotte Rigaud Lambros Tselikas Peggy Dartigues Alina Danu Amélie Bigorgne Veronique Minard David Ghez Aurélien Marabelle Laurence Zitvogel Vincent Ribrag CD8+ T Lymphocytes Immune Depletion and LAG-3 Overexpression in Hodgkin Lymphoma Tumor Microenvironment Exposed to Anti-PD-1 Immunotherapy |
| description |
<i>Background</i>: Resistance to anti-PD-1 remains a considerable clinical challenge for the treatment of patients with classical Hodgkin lymphoma (cHL), and mechanisms of anti-PD-1 resistance remain unknown. This pilot study aims to investigate the tumor microenvironment in patients with cHL relapsing after anti-PD-1. <i>Methods</i>: This study investigated tumor samples of eight patients with cHL, including four patients exposed to anti-PD-1 with a paired longitudinal histological analysis before and after anti-PD-1, and four patients not exposed to anti-PD-1 who served as control for the cellular biological investigations. Fresh cells tumor microenvironment analysis included phenotypic characterization of their T cell surfaces immune checkpoint markers PD-1, PD-L1, ICOS, TIM-3, LAG-3, 41-BB and BTLA. Tumor tissues immunohistochemistry staining included CD30, CD4, CD8, CD68, CD163, PD-L1, PD-1, LAG-3 and TIM-3. <i>Findings</i>: Paired longitudinal tumor tissues analysis in the tumor microenvironment found a CD8+ lymphocytes tumor depletion and an increase of LAG-3 staining after anti-PD-1 exposure. The fresh cells analysis of the tumor microenvironment in patients exposed to anti-PD-1 found CD8+ lymphocyte depletion, with an elevated CD4+/CD8+ lymphocytes ratio (median ratio 9.77 in exposed anti-PD-1 versus 2.39 in not-exposed anti-PD-1 patients; <i>p</i> = 0.0943). On the cell surfaces of CD4+ lymphocytes, the median positive expression of LAG-3 was significantly higher in the samples exposed to anti-PD-1 compared to the controls (15.05 [IQR:17.91–10.65] versus 3.84 [IQR 1.87–6.57]; <i>p</i> = 0.0376). <i>Interpretation</i>: This pilot study proposes hypotheses for understanding the resistance to immunotherapies in patients with Hodgkin lymphoma. Hodgkin lymphoma exposed to anti-PD-1 correlated in tumor microenvironment with an immune depletion of CD8+ T lymphocytes and overexpression of LAG-3 on CD4+ helper T lymphocytes. |
| format |
article |
| author |
Jean-Marie Michot Severine Mouraud Julien Adam Julien Lazarovici Camille Bigenwald Charlotte Rigaud Lambros Tselikas Peggy Dartigues Alina Danu Amélie Bigorgne Veronique Minard David Ghez Aurélien Marabelle Laurence Zitvogel Vincent Ribrag |
| author_facet |
Jean-Marie Michot Severine Mouraud Julien Adam Julien Lazarovici Camille Bigenwald Charlotte Rigaud Lambros Tselikas Peggy Dartigues Alina Danu Amélie Bigorgne Veronique Minard David Ghez Aurélien Marabelle Laurence Zitvogel Vincent Ribrag |
| author_sort |
Jean-Marie Michot |
| title |
CD8+ T Lymphocytes Immune Depletion and LAG-3 Overexpression in Hodgkin Lymphoma Tumor Microenvironment Exposed to Anti-PD-1 Immunotherapy |
| title_short |
CD8+ T Lymphocytes Immune Depletion and LAG-3 Overexpression in Hodgkin Lymphoma Tumor Microenvironment Exposed to Anti-PD-1 Immunotherapy |
| title_full |
CD8+ T Lymphocytes Immune Depletion and LAG-3 Overexpression in Hodgkin Lymphoma Tumor Microenvironment Exposed to Anti-PD-1 Immunotherapy |
| title_fullStr |
CD8+ T Lymphocytes Immune Depletion and LAG-3 Overexpression in Hodgkin Lymphoma Tumor Microenvironment Exposed to Anti-PD-1 Immunotherapy |
| title_full_unstemmed |
CD8+ T Lymphocytes Immune Depletion and LAG-3 Overexpression in Hodgkin Lymphoma Tumor Microenvironment Exposed to Anti-PD-1 Immunotherapy |
| title_sort |
cd8+ t lymphocytes immune depletion and lag-3 overexpression in hodgkin lymphoma tumor microenvironment exposed to anti-pd-1 immunotherapy |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/da9c5b5b2f4d417bba91f68888616b65 |
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