ArticleMolecular cancer therapeutics2021
T Cell-Mediated Antitumor Immunity Cooperatively Induced By TGFβR1 Antagonism and Gemcitabine Counteracts Reformation of the Stromal Barrier in Pancreatic Cancer.
Article in Molecular cancer therapeutics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
15 citing papers in PubMed, 18 citations in OpenAlex.
- Single-Cell Sequencing Unravels Pancreatic Cancer: Novel Technologies Reveal Novel Aspects of Cellular Heterogeneity and Inform Therapeutic Strategies.Biomedicines · 2025Review
- Exploration of the current status and trends of pancreatic cancer immune cells in the past 30 years: a bibliometric analysis.Discover oncology · 2025Article
- Emerging therapeutics targeting tumor-associated macrophages for the treatment of solid organ cancers.Expert opinion on emerging drugs · 2025Review
- Benign non-immune cells in tumor microenvironment.Frontiers in immunology · 2025Review
- Targeting heterogeneous tumor microenvironments in pancreatic cancer mouse models of metastasis by TGF-β depletion.JCI insight · 2024Article
- Iron-loaded cancer-associated fibroblasts induce immunosuppression in prostate cancer.Nature communications · 2024Article
- Interactions between cancer-associated fibroblasts and T-cells: functional crosstalk with targeting and biomarker potential.Upsala journal of medical sciences · 2024Review
- Transforming Growth Factor-β Blockade in Pancreatic Cancer Enhances Sensitivity to Combination Chemotherapy.Gastroenterology · 2023Article
- Single-cell transcriptome analysis for cancer and biology of the pancreas: A review on recent progress.Frontiers in genetics · 2023Review
- The difficulty in translating the preclinical success of combined TGFβ and immune checkpoint inhibition to clinical trial.EBioMedicine · 2022Review
- Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma.Cell death & disease · 2022Review
- Emerging kinase inhibitors for the treatment of pancreatic ductal adenocarcinoma.Expert opinion on emerging drugs · 2022Review
- The immune modifying effects of chemotherapy and advances in chemo-immunotherapy.Pharmacology & therapeutics · 2022Review
- Combinatorial regimens of chemotherapeutic agents: A new perspective on raising the heat of the tumor immune microenvironment.Frontiers in pharmacology · 2022Review
- Cancer Associated Fibroblasts - An Impediment to Effective Anti-Cancer T Cell Immunity.Frontiers in immunology · 2022Review
Corrections and comments
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Authors and funding
22 authors at 9 institutions in 5 countries.
Funding
Abstract
The desmoplastic stroma of pancreatic cancers forms a physical barrier that impedes intratumoral drug delivery. Attempts to modulate the desmoplastic stroma to increase delivery of administered chemotherapy have not shown positive clinical results thus far, and preclinical reports in which chemotherapeutic drugs were coadministered with antistromal therapies did not universally demonstrate increased genotoxicity despite increased intratumoral drug levels. In this study, we tested whether TGFβ antagonism can break the stromal barrier, enhance perfusion and tumoral drug delivery, and interrogated cellular and molecular mechanisms by which the tumor prevents synergism with coadministered gemcitabine. TGFβ inhibition in genetically engineered murine models (GEMM) of pancreas cancer enhanced tumoral perfusion and increased intratumoral gemcitabine levels. However, tumors rapidly adapted to TGFβ-dependent stromal modulation, and intratumoral perfusion returned to pre-treatment levels upon extended TGFβ inhibition. Perfusion was governed by the phenotypic identity and distribution of cancer-associated fibroblasts (CAF) with the myelofibroblastic phenotype (myCAFs), and myCAFs which harbored unique genomic signatures rapidly escaped the restricting effects of TGFβ inhibition. Despite the reformation of the stromal barrier and reversal of initially increased intratumoral exposure levels, TGFβ inhibition in cooperation with gemcitabine effectively suppressed tumor growth via cooperative reprogramming of T regulatory cells and stimulation of CD8 T cell-mediated antitumor activity. The antitumor activity was further improved by the addition of anti-PD-L1 immune checkpoint blockade to offset adaptive PD-L1 upregulation induced by TGFβ inhibition. These findings support the development of combined antistroma anticancer therapies capable of impacting the tumor beyond the disruption of the desmoplastic stroma as a physical barrier to improve drug delivery.
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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.