ArticleJournal for immunotherapy of cancer2022
Insufficiency of compound immune checkpoint blockade to overcome engineered T cell exhaustion in pancreatic cancer.
Article in Journal for immunotherapy of cancer, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 12 citations in OpenAlex.
- Safe and Localized Lentiviral Gene Delivery via Injectable Mesoporous Scaffolds for Potent Antitumor Immunity.Advanced materials (Deerfield Beach, Fla.) · 2026Article
- T cell immunotherapy for solid tumors: limitations, progress, and future prospects.Frontiers in immunology · 2026Review
- Triple checkpoint blockade of PD-1, Tim-3, and Lag-3 enhances adoptive T cell immunotherapy in a mouse model of ovarian cancer.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- A TGF-βR/IL-2R immunomodulatory fusion protein transforms immunosuppression into T cell activation to enhance adoptive T cell therapy.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Multi-engineered T cell vaccine boosting TCR-T cell therapy enhances anti-tumor function and eradicates heterogeneous solid tumors.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Multifunctional HBc Virus-Like Particles Reprogram Immunosuppressive Macrophages and Potentiate CD8International journal of nanomedicine · 2025Article
- New avenues for the treatment of immunotherapy-resistant pancreatic cancer.World journal of gastrointestinal oncology · 2024Review
- Polarization of Cancer-Associated Macrophages Maneuver Neoplastic Attributes of Pancreatic Ductal Adenocarcinoma.Cancers · 2023Review
- The role of molecular testing in pancreatic cancer.Therapeutic advances in gastroenterology · 2023Review
- Preclinical studies performed in appropriate models could help identify optimal timing of combined chemotherapy and immunotherapy.Frontiers in immunology · 2023Review
- Self-delivery of TIGIT-blocking scFv enhances CAR-T immunotherapy in solid tumors.Frontiers in immunology · 2023Article
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundAchieving robust responses with adoptive cell therapy for the treatment of the highly lethal pancreatic ductal adenocarcinoma (PDA) has been elusive. We previously showed that T cells engineered to express a mesothelin-specific T cell receptor (TCR
methodsHere, we investigated the role of immune checkpoints in mediating TCR engineered T cell dysfunction in a genetically engineered PDA mouse model. The fate of engineered T cells that were either deficient in PD-1, or transferred concurrent with antibodies blocking PD-L1 and/or additional immune checkpoints, were tracked to evaluate persistence, functionality, and antitumor activity at day 8 and day 28 post infusion. We performed RNAseq on engineered T cells isolated from tumors and compared differentially expressed genes to prototypical endogenous exhausted T cells.
resultsPD-L1 pathway blockade and/or simultaneous blockade of multiple coinhibitory receptors during adoptive cell therapy was insufficient to prevent engineered T cell dysfunction in autochthonous PDA yet resulted in subclinical activity in the lung, without enhancing anti-tumor immunity. Gene expression analysis revealed that ex vivo TCR engineered T cells markedly differed from in vivo primed endogenous effector T cells which can respond to immune checkpoint inhibitors. Early after transfer, intratumoral TCR engineered T cells acquired a similar molecular program to prototypical exhausted T cells that arise during chronic viral infection, but the molecular programs later diverged. Intratumoral engineered T cells exhibited decreased effector and cell cycle genes and were refractory to TCR signaling.
conclusionsAbrogation of PD-1 signaling is not sufficient to overcome TCR engineered T cell dysfunction in PDA. Our study suggests that contributions by both the differentiation pathways induced during the ex vivo T cell engineering process and intratumoral suppressive mechanisms render engineered T cells dysfunctional and resistant to rescue by blockade of immune checkpoints.
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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.