The TGF-R1 inhibitor galunisertib re-shapes the PDAC-TME by limiting decidual-like natural killer cells polarization
Research article published in Cell death & disease (2026)
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality worldwide. Natural Killer (NKs) cells are pivotal for tumor surveillance but are dysfunctional in PDAC. We evaluated whether pharmacological blockade of TGF-β1/TGF-βR1 axis in PDAC cells and cancer-associated fibroblasts (CAFs) could modulate NK polarization via soluble factors. The phenotype/functions of NKs from PDAC patients versus healthy controls (HC) were compared, and the polarization state of NKs exposed to the conditioned media of PDAC cells and fibroblasts was evaluated by flow cytometry. The ability of galunisertib (GAL) to reverse NK dysfunction in immunocompetent mice orthotopically implanted with FC1199 PDAC cells was evaluated. PDAC patients showed higher TGF-β1/ TGF-βR1 levels than HC, with worse outcomes in TGF-β1high/TGF-βR1high patients. Circulating CD9+ NKs were expanded in PDAC patients compared with HC and exhibited a pro-angiogenic secretome and higher pro-angiogenic activities in vitro and in vivo (leech Hirudo verbana), compared to the CD9- NK cells. PDAC cells and CAF induced a CD9+-decidual-like phenotype, also impairing NK degranulation. GAL treatment restrains PDAC cell/CAF-induced NK anergy, restoring their cytotoxicity. Also, TGFβ-R1 knockdown in PDAC cells exhibited the capability to limit the generation of decidual-like NKs, while restoring their antitumor ability, via soluble factors. Secretome profiling of BxPC3 and MIAPaCA2 PDAC cell lines and CAFs showed that GAL downregulated the release of several growth, angiogenic, and immunoregulatory factors, including FGF2, HGF, IL11, PLGF, EGFR, and VEGF. In vivo in orthotopic tumors formed by FC1199 cells GAL decreased CD9+-NK frequency, promoted M1-macrophage polarization, and activated NK and CD8+T-cells, together with a significant reduction of tumor weight, fibrosis and inhibition of angiogenesis. Our study identifies CD9+NKs as a novel cell subset expanded in PDAC and underscores the role of TGF-β1/TGF-βR1 signalling in promoting a pro-tumoral NKs GAL-treatment emerges as immunomodulator able in re-educating pro-tumor NKs cells in PDAC.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Resumen
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality worldwide.
Por qué esto importa para la hirudoterapia
Este estudio examinó el bloqueo de TGF-β1/TGF-βR1 mediante galunisertib en el adenocarcinoma ductal pancreático, centrándose en la polarización de células NK CD9+ de tipo decidual y la remodelación del microambiente tumoral. Entre los métodos, se comparó la actividad angiogénica de las células NK CD9+ frente a las CD9- mediante un ensayo de angiogénesis in vivo en la sanguijuela Hirudo verbana. El estudio halló que las NK CD9+ mostraban actividad proangiogénica y que el galunisertib restauró la citotoxicidad de las NK y redujo el crecimiento tumoral y la angiogénesis en ratones ortotópicos. Para el dominio de la ASH, Hirudo verbana aparece como un modelo de bioensayo de angiogénesis in vivo, lo cual es tangencialmente relevante porque demuestra un uso científico de una especie de sanguijuela medicinal. Sin embargo, el estudio no trata sobre hirudoterapia; la sanguijuela se utiliza únicamente como organismo sustituto de ensayo para medir respuestas angiogénicas, lo que hace que la conexión con la terapia clínica con sanguijuelas o el secretoma de la sanguijuela sea indirecta y limitada.
Citación
The TGF-R1 inhibitor galunisertib re-shapes the PDAC-TME by limiting decidual-like natural killer cells polarization
Cucchiara M et al. · Cell death & disease, 2026
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Añadido a la biblioteca ASH: May 27, 2026 · Última actualización del sitio: 18 de junio de 2026