ArticleNature immunology2024
The BTLA-HVEM axis restricts CAR T cell efficacy in cancer.
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Article in Nature immunology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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33citing papers in PubMed
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Who cites it
33 citing papers in PubMed.
- A Tumor-Boundary Niche Enriched for PD-1Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Investigating the role of costimulatory domains in enhancing CAR-T cell persistence in TNBC.Cancer gene therapy · 2026Review
- A guide to CAR T cell therapies: development, current status and future prospects.Nature reviews. Immunology · 2026Review
- Soluble immune checkpoints reflect immune activation and treatment response in high-risk systemic sclerosis patients treated with plasma exchange.Journal of translational autoimmunity · 2026Article
- Triple-Negative Breast Cancer: Molecular Subtypes; Immune Escape; Limitations of Current Immunotherapy; and the BTLA/HVEM/CD160 Axis as an Emerging Target.Current issues in molecular biology · 2026Review
- Single-cell dissection of pleural and systemic immunity uncovers pathogen-specific immune reprogramming in tuberculosis versus lung adenocarcinoma.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- Decoding signaling architectures: CAR versus TCR dynamics in solid tumor immunotherapy.Acta biochimica et biophysica Sinica · 2026Review
- HVEM costimulatory domain boosts CAR T cell efficacy against solid tumors via enhanced TRAF-mediated TNF signaling.Cell communication and signaling : CCS · 2026Article
- Post-translational modifications of immune checkpoints: molecular mechanisms, tumor microenvironment remodeling, and therapeutic implications.Journal of biomedical science · 2026Review
- PTPN6/SHP-1 in autoimmune disease: immune tolerance, regulatory mechanisms, and therapeutic targeting.Frontiers in immunology · 2026Review
- CD244 overexpression indicates NK cell dysfunction and tumor progression in diffuse large B-cell lymphoma.Frontiers in immunology · 2026Article
- Rewriting CAR-T cell fate: CRISPR/Cas gene editing for solid tumor therapy.Frontiers in immunology · 2026Review
- A multi-omics integrative analyses revealsFrontiers in pharmacology · 2026Article
- Research progress on resistance mechanisms to CAR-T cell therapy in diffuse large B-cell lymphoma.Frontiers in oncology · 2026Review
- Improving CAR T cell therapy against malignancies through gene knock-down/out strategies: a systematic review.Cancer cell international · 2025Review
- Next-generation immunotherapies for head and neck squamous cell carcinoma: targeting novel immune checkpoints.Annals of medicine · 2025Review
- Manufacturing of CRISPR-edited primary mouse CAR T cells for cancer immunotherapy.Nature protocols · 2025Article
- BTLA: An Emerging Immune Checkpoint Target in Cancer Immunotherapy.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Current status of chimeric antigen receptor T cell therapy and its exhaustion mechanism.Immunotherapy · 2025Review
- The role of tumor necrosis factor receptor superfamily in cancer: insights into oncogenesis, progression, and therapeutic strategies.NPJ precision oncology · 2025Review
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Authors and funding
38 authors.
Puneeth GuruprasadDepartment of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
Alberto CarturanCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Yunlin ZhangCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Jong Hyun ChoDepartment of Pathology, Immunology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA.
Kingsley Gideon KumashieDivision of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0001-7713-1779
Ruchi P PatelCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0001-8366-1928
Ki-Hyun KimR&D Center, AbClon Inc., Seoul, Republic of Korea.
Jong-Seo LeeR&D Center, AbClon Inc., Seoul, Republic of Korea.
Yoon LeeR&D Center, AbClon Inc., Seoul, Republic of Korea.
Jong Hoon KimR&D Center, AbClon Inc., Seoul, Republic of Korea.
Junho ChungCancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Akshita JoshiCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Ivan CohenCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Maksim ShestovCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Guido GhilardiCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Jaryse HarrisCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Raymone PajarilloCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Mathew AngelosCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Yong Gu LeeCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Shan LiuDepartment of Microbiology, University of Pennsylvania, Philadelphia, PA, USA.
Jesse RodriguezCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Michael WangCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Hatcher J BallardDepartment of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Aasha GuptaCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Ositadimma H UgwuanyiCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Seok Jae Albert HongCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Audrey C Bochi-LayecCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Christopher T SauterCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Linhui ChenCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Luca ParuzzoCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-6505-0194
Shane KammermanDivision of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Olga ShestovaCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Dongfang LiuDepartment of Pathology, Immunology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA.ORCID http://orcid.org/0000-0002-7295-8088
Laura A VellaDivision of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Stephen J SchusterDepartment of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Jakub SvobodaDepartment of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Patrizia PorazziCenter for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Marco RuellaDepartment of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. mruella@upenn.edu.ORCID http://orcid.org/0000-0003-4301-5811
Funding
Project 3: Combinatorial and gene-editing approaches to enhance the efficacy of CAR T cell therapy of multiple myeloma.P01CA214278 · NCI · UNIVERSITY OF PENNSYLVANIA · PI Joseph Anthony Fraietta · 2017 to 2026
$26.8MMODULATION OF CD5 SIGNALING TO ENHANCE ADOPTIVE T-CELL THERAPIES FOR CANCERR37CA262362 · NCI · UNIVERSITY OF PENNSYLVANIA · PI Marco Ruella · 2022 to 2026
$2.6MResistance To Targeted Immunotherapies:CART19 as a ParadigmR00CA212302 · NCI · UNIVERSITY OF PENNSYLVANIA · PI RUELLA, MARCO · 2018 to 2020
$608kFoundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) AI130197Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) CA267368NCI NIH HHS P01 CA214278NCI NIH HHS R37 CA262362U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R00-CA212302
Abstract
The efficacy of T cell-based immunotherapies is limited by immunosuppressive pressures in the tumor microenvironment. Here we show a predominant role for the interaction between BTLA on effector T cells and HVEM (TNFRSF14) on immunosuppressive tumor microenvironment cells, namely regulatory T cells. High BTLA expression in chimeric antigen receptor (CAR) T cells correlated with poor clinical response to treatment. Therefore, we deleted BTLA in CAR T cells and show improved tumor control and persistence in models of lymphoma and solid malignancies. Mechanistically, BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2, upon trans engagement with HVEM. BTLA knockout thus promotes CAR signaling and subsequently enhances effector function. Overall, these data indicate that the BTLA-HVEM axis is a crucial immune checkpoint in CAR T cell immunotherapy and warrants the use of strategies to overcome this barrier.
Indexed as
Immunotherapy, AdoptiveReceptors, Chimeric AntigenReceptors, ImmunologicReceptors, Tumor Necrosis Factor, Member 14Tumor MicroenvironmentAnimalsCell Line, TumorHumansMiceMice, KnockoutNeoplasmsSignal TransductionT-Lymphocytes, RegulatoryBTLA protein, humanBTLA protein, mouseReceptors, Chimeric AntigenReceptors, ImmunologicReceptors, Tumor Necrosis Factor, Member 14TNFRSF14 protein, humanTnfrsf14 protein, mouse
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.