Cd8+ t lymphocytes immune depletion and lag-3 overexpression in hodgkin lymphoma tumor microenvironment exposed to anti-pd-1 immunotherapy

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

doi:10.3390/cancers13215487

Cd8+ t lymphocytes immune depletion and lag-3 overexpression in hodgkin lymphoma tumor microenvironment exposed to anti-pd-1 immunotherapy

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

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Résumé

Background: 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. Methods: 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. Findings: 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; p = 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]; p = 0.0376). Interpretation: 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.

langue originale	Anglais
Numéro d'article	5487
journal	Cancers
Volume	13
Numéro de publication	21
Les DOIs	https://doi.org/10.3390/cancers13215487
état	Publié - 1 nov. 2021

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10.3390/cancers13215487

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Michot, J. M., Mouraud, S., Adam, J., Lazarovici, J., Bigenwald, C., Rigaud, C., Tselikas, L., Dartigues, P., Danu, A., Bigorgne, A., Minard, V., Ghez, D., Marabelle, A., Zitvogel, L., & Ribrag, V. (2021). Cd8+ t lymphocytes immune depletion and lag-3 overexpression in hodgkin lymphoma tumor microenvironment exposed to anti-pd-1 immunotherapy. Cancers, 13(21), Article 5487. https://doi.org/10.3390/cancers13215487

@article{02527a89ac8a4de7993f8f0072771f65,

title = "Cd8+ t lymphocytes immune depletion and lag-3 overexpression in hodgkin lymphoma tumor microenvironment exposed to anti-pd-1 immunotherapy",

abstract = "Background: 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. Methods: 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. Findings: 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; p = 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]; p = 0.0376). Interpretation: 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.",

keywords = "Anti-PD-1, Hodgkin lymphoma, Immune checkpoint inhibitors, LAG-3",

author = "Michot, {Jean Marie} and Severine Mouraud and Julien Adam and Julien Lazarovici and Camille Bigenwald and Charlotte Rigaud and Lambros Tselikas and Peggy Dartigues and Alina Danu and Am{\'e}lie Bigorgne and Veronique Minard and David Ghez and Aur{\'e}lien Marabelle and Laurence Zitvogel and Vincent Ribrag",

note = "Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = nov,

day = "1",

doi = "10.3390/cancers13215487",

language = "English",

volume = "13",

journal = "Cancers",

issn = "2072-6694",

number = "21",

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Michot, JM, Mouraud, S, Adam, J, Lazarovici, J, Bigenwald, C, Rigaud, C, Tselikas, L, Dartigues, P, Danu, A, Bigorgne, A, Minard, V, Ghez, D, Marabelle, A, Zitvogel, L & Ribrag, V 2021, 'Cd8+ t lymphocytes immune depletion and lag-3 overexpression in hodgkin lymphoma tumor microenvironment exposed to anti-pd-1 immunotherapy', Cancers, VOL. 13, Numéro 21, 5487. https://doi.org/10.3390/cancers13215487

TY - JOUR

T1 - Cd8+ t lymphocytes immune depletion and lag-3 overexpression in hodgkin lymphoma tumor microenvironment exposed to anti-pd-1 immunotherapy

AU - Michot, Jean Marie

AU - Mouraud, Severine

AU - Adam, Julien

AU - Lazarovici, Julien

AU - Bigenwald, Camille

AU - Rigaud, Charlotte

AU - Tselikas, Lambros

AU - Dartigues, Peggy

AU - Danu, Alina

AU - Bigorgne, Amélie

AU - Minard, Veronique

AU - Ghez, David

AU - Marabelle, Aurélien

AU - Zitvogel, Laurence

AU - Ribrag, Vincent

PY - 2021/11/1

Y1 - 2021/11/1

N2 - Background: 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. Methods: 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. Findings: 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; p = 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]; p = 0.0376). Interpretation: 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.

AB - Background: 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. Methods: 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. Findings: 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; p = 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]; p = 0.0376). Interpretation: 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.

KW - Anti-PD-1

KW - Hodgkin lymphoma

KW - Immune checkpoint inhibitors

KW - LAG-3

UR - http://www.scopus.com/inward/record.url?scp=85118217378&partnerID=8YFLogxK

U2 - 10.3390/cancers13215487

DO - 10.3390/cancers13215487

M3 - Article

AN - SCOPUS:85118217378

SN - 2072-6694

VL - 13

JO - Cancers

JF - Cancers

IS - 21

M1 - 5487

ER -