ArticleMolecular therapy : the journal of the American Society of Gene Therapy2018
CD28-ζ CAR T Cells Resist TGF-β Repression through IL-2 Signaling, Which Can Be Mimicked by an Engineered IL-7 Autocrine Loop.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 85 citations in OpenAlex.
- The Conflicting Role of Myeloid Cells in CAR T-Cell Therapy.Cancer research · 2026Review
- CAR-T cell therapy for pediatric solid tumors: armored CAR-T cells and beyond.Cancer metastasis reviews · 2026Review
- Microenvironmental regulation of solid tumour resistance to CAR T cell therapy.Nature reviews. Immunology · 2026Review
- CAR T-cells for the treatment of CNS malignancies.Frontiers in immunology · 2026Review
- CAR T Cell Therapy in Lung Cancer: Overcoming Tumor Microenvironment-Mediated Barriers.International journal of biological sciences · 2026Review
- Enhanced anti-liver tumor efficacy of chimeric antigen receptor-T cells via SATB1 modulation.Cell death & disease · 2025Article
- Challenges and limitations of chimeric antigen receptor T-cell therapies in solid tumors: why are approvals restricted to hematologic malignancies?Journal of hematology & oncology · 2025Review
- A Newly Developed TGF-Β-Responsive CAR T Cell for Enhanced Proliferation and Cytokine Secretion.Advanced pharmaceutical bulletin · 2025Article
- Constructing the cure: engineering the next wave of antibody and cellular immune therapies.Journal for immunotherapy of cancer · 2025Review
- Discordant CAR-T cell signaling: implications of divergence from physiological T cell activation.Journal of translational medicine · 2025Review
- Article
- Potentiating CAR-T cell function in the immunosuppressive tumor microenvironment by inverting the TGF-β signal.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- SMAD4 Regulates the Expression of LCK Affecting Chimeric Antigen Receptor-T Cells Proliferation Through PI3K/Akt Signaling Pathway.Journal of cellular physiology · 2025Article
- CAR-T cell therapy: Advances in digestive system malignant tumors.Molecular therapy. Oncology · 2024Review
- The development and application of chimeric antigen receptor natural killer (CAR-NK) cells for cancer therapy: current state, challenges and emerging therapeutic advances.Experimental hematology & oncology · 2024Review
- BCKDK modification enhances the anticancer efficacy of CAR-T cells by reprogramming branched chain amino acid metabolism.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Activation of Cell-Intrinsic Signaling in CAR-T Cells via a Chimeric IL7R Domain.Cancer research communications · 2024Article
- Review
- CAR-T cell manufacturing landscape-Lessons from the past decade and considerations for early clinical development.Molecular therapy. Methods & clinical development · 2024Review
- Programmable synthetic receptors: the next-generation of cell and gene therapies.Signal transduction and targeted therapy · 2024Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Adoptive cell therapy with chimeric antigen receptor (CAR)-redirected T cells induced spectacular regressions of leukemia and lymphoma, however, failed so far in the treatment of solid tumors. A cause is thought to be T cell repression through TGF-β, which is massively accumulating in the tumor tissue. Here, we show that T cells with a CD28-ζ CAR, but not with a 4-1BB-ζ CAR, resist TGF-β-mediated repression. Mechanistically, LCK activation and consequently IL-2 release and autocrine IL-2 receptor signaling mediated TGF-β resistance; deleting the LCK-binding motif in the CD28 CAR abolished both IL-2 secretion and TGF-β resistance, while IL-2 add-back restored TGF-β resistance. Other γ-cytokines like IL-7 and IL-15 could replace IL-2 in this context. This is demonstrated by engineering IL-2 deficient CD28ΔLCK-ζ CAR T cells with a hybrid IL-7 receptor to provide IL-2R β chain signaling upon IL-7 binding. Such modified T cells showed improved CAR T cell activity against TGF-β
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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.