ArticleProceedings of the National Academy of Sciences of the United States of America2023
Inefficient exploitation of accessory receptors reduces the sensitivity of chimeric antigen receptors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 58 citations in OpenAlex.
- Functional screening of TCR-like antibodies using STAR-T cell library for cancer immunotherapy.EMBO molecular medicine · 2026Article
- The TCR in CAR T cell therapy: use it or lose it?Cancer gene therapy · 2026Review
- Balancing the efficacy and safety of chimeric antigen receptor T-cell therapy by affinity combination.Nature communications · 2026Article
- DUSP6 ablation restores CAR T-cell fitness impaired by tumor CD58 loss through invigoration of AP-1 signaling.Signal transduction and targeted therapy · 2026Article
- CD2 costimulation bridges potent CAR-induced cytolysis and durable persistence.Journal for immunotherapy of cancer · 2026Article
- Affinity and costimulatory architecture-associated toxicity in mesothelin-targeted TCR-mimetic CAR-T cells.Frontiers in immunology · 2026Article
- Adapter-based allogeneic CAR T cells to overcome antigen escape in solid tumors.Frontiers in immunology · 2026Review
- Targeting the roots of myeloid malignancies with T cell receptors.Nature reviews. Cancer · 2025Review
- Directed evolution of LaccID for cell surface proximity labeling and electron microscopy.Nature chemical biology · 2025Article
- Engineering T cells with a membrane-tethered version of SLP-76 overcomes antigen-low resistance to CAR T cell therapy.Nature cancer · 2025Article
- A yeast surface display platform for characterizing CAR T cell responses to cancer antigens.Nature communications · 2025Article
- Constructing the cure: engineering the next wave of antibody and cellular immune therapies.Journal for immunotherapy of cancer · 2025Review
- Platforms for studying cell-cell recognition by immune cells.Immunology and cell biology · 2025Review
- Discordant CAR-T cell signaling: implications of divergence from physiological T cell activation.Journal of translational medicine · 2025Review
- Article
- Solution structure and synaptic analyses reveal determinants of bispecific T cell engager potency.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- T-bet overexpression enhances CAR T cell effector functions and antigen sensitivity.Journal for immunotherapy of cancer · 2025Article
- RESET: A TCR-coupled antigen receptor with superior targeting sensitivity and reversible drug-regulated anti-tumor activity.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Design of sensitive monospecific and bispecific synthetic chimeric T cell receptors for cancer therapy.Nature cancer · 2025Article
- Gene editing of CD3 epsilon to redirect regulatory T cells for adoptive T cell transfer.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Chimeric antigen receptors (CARs) can redirect T cells to target abnormal cells, but their activity is limited by a profound defect in antigen sensitivity, the source of which remains unclear. Here, we show that CARs have a > 100-fold lower antigen sensitivity compared to the T cell receptor (TCR) when antigen is presented on antigen-presenting cells (APCs) but nearly identical sensitivity when antigen is presented as purified protein. We next systematically measured the impact of engaging important T cell accessory receptors (CD2, LFA-1, CD28, CD27, and 4-1BB) on antigen sensitivity by adding their purified ligands. Unexpectedly, we found that engaging CD2 or LFA-1 improved the antigen sensitivity of the TCR by 125- and 22-fold, respectively, but improved CAR sensitivity by only < 5-fold. This differential effect of CD2 and LFA-1 engagement on the TCR vs. CAR was confirmed using APCs. We found that sensitivity to antigen can be partially restored by fusing the CAR variable domains to the TCR CD3
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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.