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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/5/e006348.full |
| _version_ | 1827892528065544192 |
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| author | Fabrice Barlesi Laurent Gorvel Daniel Olive Clemence Demerle Laurent Greillier Sonia Pastor Geoffrey Guittard Jacques A Nunes Marielle Mello Clara Degos Ana Zarubica Fabien Angelis Frédéric Fiore Bernard Malissen Hervé Luche |
| author_facet | Fabrice Barlesi Laurent Gorvel Daniel Olive Clemence Demerle Laurent Greillier Sonia Pastor Geoffrey Guittard Jacques A Nunes Marielle Mello Clara Degos Ana Zarubica Fabien Angelis Frédéric Fiore Bernard Malissen Hervé Luche |
| author_sort | Fabrice Barlesi |
| collection | DOAJ |
| 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)). |
| first_indexed | 2024-03-12T21:41:57Z |
| format | Article |
| id | doaj.art-fdfc15c4c1eb4b6cb203ba727e691a4f |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T21:41:57Z |
| publishDate | 2023-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-fdfc15c4c1eb4b6cb203ba727e691a4f2023-07-26T21:40:06ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-05-0111510.1136/jitc-2022-006348Anti-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 tumorsFabrice Barlesi0Laurent Gorvel1Daniel Olive2Clemence Demerle3Laurent Greillier4Sonia Pastor5Geoffrey Guittard6Jacques A Nunes7Marielle Mello8Clara Degos9Ana Zarubica10Fabien Angelis11Frédéric Fiore12Bernard Malissen13Hervé Luche144Institut Gustave Roussy, Villejuif, FranceDepartment of Immunomonitoring, Institut Paoli-Calmettes, Marseille, FranceDepartment of Immunomonitoring, Institut Paoli-Calmettes, Marseille, FranceDepartment of Immunomonitoring, Institut Paoli-Calmettes, Marseille, FranceAix-Marseille University, Marseille, FranceTeam Immunity and Cancer, Centre de Recherche en Cancérologie de Marseille, Marseille, France3Cancer Research Center Marseille, Marseille, FranceTeam Immunity and Cancer, Centre de Recherche en Cancérologie de Marseille, Marseille, FranceCentre d`Immunophénomique—CIPHE (PHENOMIN), Marseille, FranceDepartment of Immunomonitoring, Institut Paoli-Calmettes, Marseille, FranceCentre d`Immunophénomique—CIPHE (PHENOMIN), Marseille, FranceCentre d`Immunophénomique—CIPHE (PHENOMIN), Marseille, FranceCentre d`Immunophénomique—CIPHE (PHENOMIN), Marseille, FranceCentre d`Immunophénomique—CIPHE (PHENOMIN), Marseille, FranceCentre d`Immunophénomique—CIPHE (PHENOMIN), Marseille, FranceBackground 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)).https://jitc.bmj.com/content/11/5/e006348.full |
| spellingShingle | Fabrice Barlesi Laurent Gorvel Daniel Olive Clemence Demerle Laurent Greillier Sonia Pastor Geoffrey Guittard Jacques A Nunes Marielle Mello Clara Degos Ana Zarubica Fabien Angelis Frédéric Fiore Bernard Malissen Hervé Luche 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 Journal for ImmunoTherapy of Cancer |
| 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 |
| url | https://jitc.bmj.com/content/11/5/e006348.full |
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