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Anti-HVEM mAb therapy improves antitumoral immunity both in vitro and in vivo, in a novel transgenic mouse model expressing human HVEM and BTLA molecules challenged with HVEM expressing tumors
BACKGROUND: Tumor necrosis factor superfamily member 14 (TNFRSF14)/herpes virus entry mediator (HVEM) is the ligand for B and T lymphocyte attenuator (BTLA) and CD160-negative immune co-signaling molecules as well as viral proteins. Its expression is dysregulated with an overexpression in tumors and...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10231015/ https://www.ncbi.nlm.nih.gov/pubmed/37230538 http://dx.doi.org/10.1136/jitc-2022-006348 |
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author | Demerlé, Clémence Gorvel, Laurent Mello, Marielle Pastor, Sonia Degos, Clara Zarubica, Ana Angelis, Fabien Fiore, Frédéric Nunes, Jacques A Malissen, Bernard Greillier, Laurent Guittard, Geoffrey Luche, Hervé Barlesi, Fabrice Olive, Daniel |
author_facet | Demerlé, Clémence Gorvel, Laurent Mello, Marielle Pastor, Sonia Degos, Clara Zarubica, Ana Angelis, Fabien Fiore, Frédéric Nunes, Jacques A Malissen, Bernard Greillier, Laurent Guittard, Geoffrey Luche, Hervé Barlesi, Fabrice Olive, Daniel |
author_sort | Demerlé, Clémence |
collection | PubMed |
description | BACKGROUND: Tumor necrosis factor superfamily member 14 (TNFRSF14)/herpes virus entry mediator (HVEM) is the ligand for B and T lymphocyte attenuator (BTLA) and CD160-negative immune co-signaling molecules as well as viral proteins. Its expression is dysregulated with an overexpression in tumors and a connection with tumors of adverse prognosis. METHODS: We developed C57BL/6 mouse models co-expressing human (hu)BTLA and huHVEM as well as antagonistic monoclonal antibodies (mAbs) that completely prevent the interactions of HVEM with its ligands. RESULTS: Here, we show that the anti-HVEM18-10 mAb increases primary human αβ-T cells activity alone (CIS-activity) or in the presence of HVEM-expressing lung or colorectal cancer cells in vitro (TRANS-activity). Anti-HVEM18-10 synergizes with antiprogrammed death-ligand 1 (anti-PD-L1) mAb to activate T cells in the presence of PD-L1-positive tumors, but is sufficient to trigger T cell activation in the presence of PD-L1-negative cells. In order to better understand HVEM18-10 effects in vivo and especially disentangle its CIS and TRANS effects, we developed a knockin (KI) mouse model expressing human BTLA (huBTLA(+/+)) and a KI mouse model expressing both huBTLA(+/+)/huHVEM(+/+) (double KI (DKI)). In vivo preclinical experiments performed in both mouse models showed that HVEM18-10 treatment was efficient to decrease human HVEM(+) tumor growth. In the DKI model, anti-HVEM18-10 treatment induces a decrease of exhausted CD8(+) T cells and regulatory T cells and an increase of effector memory CD4(+) T cells within the tumor. Interestingly, mice which completely rejected tumors (±20%) did not develop tumors on rechallenge in both settings, therefore showing a marked T cell-memory phenotype effect. CONCLUSIONS: Altogether, our preclinical models validate anti-HVEM18-10 as a promising therapeutic antibody to use in clinics as a monotherapy or in combination with existing immunotherapies (antiprogrammed cell death protein 1/anti-PD-L1/anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4)). |
format | Online Article Text |
id | pubmed-10231015 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-102310152023-06-01 Anti-HVEM mAb therapy improves antitumoral immunity both in vitro and in vivo, in a novel transgenic mouse model expressing human HVEM and BTLA molecules challenged with HVEM expressing tumors Demerlé, Clémence Gorvel, Laurent Mello, Marielle Pastor, Sonia Degos, Clara Zarubica, Ana Angelis, Fabien Fiore, Frédéric Nunes, Jacques A Malissen, Bernard Greillier, Laurent Guittard, Geoffrey Luche, Hervé Barlesi, Fabrice Olive, Daniel J Immunother Cancer Basic Tumor Immunology BACKGROUND: Tumor necrosis factor superfamily member 14 (TNFRSF14)/herpes virus entry mediator (HVEM) is the ligand for B and T lymphocyte attenuator (BTLA) and CD160-negative immune co-signaling molecules as well as viral proteins. Its expression is dysregulated with an overexpression in tumors and a connection with tumors of adverse prognosis. METHODS: We developed C57BL/6 mouse models co-expressing human (hu)BTLA and huHVEM as well as antagonistic monoclonal antibodies (mAbs) that completely prevent the interactions of HVEM with its ligands. RESULTS: Here, we show that the anti-HVEM18-10 mAb increases primary human αβ-T cells activity alone (CIS-activity) or in the presence of HVEM-expressing lung or colorectal cancer cells in vitro (TRANS-activity). Anti-HVEM18-10 synergizes with antiprogrammed death-ligand 1 (anti-PD-L1) mAb to activate T cells in the presence of PD-L1-positive tumors, but is sufficient to trigger T cell activation in the presence of PD-L1-negative cells. In order to better understand HVEM18-10 effects in vivo and especially disentangle its CIS and TRANS effects, we developed a knockin (KI) mouse model expressing human BTLA (huBTLA(+/+)) and a KI mouse model expressing both huBTLA(+/+)/huHVEM(+/+) (double KI (DKI)). In vivo preclinical experiments performed in both mouse models showed that HVEM18-10 treatment was efficient to decrease human HVEM(+) tumor growth. In the DKI model, anti-HVEM18-10 treatment induces a decrease of exhausted CD8(+) T cells and regulatory T cells and an increase of effector memory CD4(+) T cells within the tumor. Interestingly, mice which completely rejected tumors (±20%) did not develop tumors on rechallenge in both settings, therefore showing a marked T cell-memory phenotype effect. CONCLUSIONS: Altogether, our preclinical models validate anti-HVEM18-10 as a promising therapeutic antibody to use in clinics as a monotherapy or in combination with existing immunotherapies (antiprogrammed cell death protein 1/anti-PD-L1/anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4)). BMJ Publishing Group 2023-05-25 /pmc/articles/PMC10231015/ /pubmed/37230538 http://dx.doi.org/10.1136/jitc-2022-006348 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Basic Tumor Immunology Demerlé, Clémence Gorvel, Laurent Mello, Marielle Pastor, Sonia Degos, Clara Zarubica, Ana Angelis, Fabien Fiore, Frédéric Nunes, Jacques A Malissen, Bernard Greillier, Laurent Guittard, Geoffrey Luche, Hervé Barlesi, Fabrice Olive, Daniel Anti-HVEM mAb therapy improves antitumoral immunity both in vitro and in vivo, in a novel transgenic mouse model expressing human HVEM and BTLA molecules challenged with HVEM expressing tumors |
title | Anti-HVEM mAb therapy improves antitumoral immunity both in vitro and in vivo, in a novel transgenic mouse model expressing human HVEM and BTLA molecules challenged with HVEM expressing tumors |
title_full | Anti-HVEM mAb therapy improves antitumoral immunity both in vitro and in vivo, in a novel transgenic mouse model expressing human HVEM and BTLA molecules challenged with HVEM expressing tumors |
title_fullStr | Anti-HVEM mAb therapy improves antitumoral immunity both in vitro and in vivo, in a novel transgenic mouse model expressing human HVEM and BTLA molecules challenged with HVEM expressing tumors |
title_full_unstemmed | Anti-HVEM mAb therapy improves antitumoral immunity both in vitro and in vivo, in a novel transgenic mouse model expressing human HVEM and BTLA molecules challenged with HVEM expressing tumors |
title_short | Anti-HVEM mAb therapy improves antitumoral immunity both in vitro and in vivo, in a novel transgenic mouse model expressing human HVEM and BTLA molecules challenged with HVEM expressing tumors |
title_sort | anti-hvem mab therapy improves antitumoral immunity both in vitro and in vivo, in a novel transgenic mouse model expressing human hvem and btla molecules challenged with hvem expressing tumors |
topic | Basic Tumor Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10231015/ https://www.ncbi.nlm.nih.gov/pubmed/37230538 http://dx.doi.org/10.1136/jitc-2022-006348 |
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