| Autor: |
Kerschbaum-Gruber, Sylvia, Kleinwächter, Ava, Popova, Katerina, Kneringer, Alexandra, Appel, Lisa-Marie, Stasny, Katharina, Röhrer, Anna, Dias, Ana Beatriz, Benedum, Johannes, Walch, Lena, Postl, Andreas, Barna, Sandra, Kratzer, Bernhard, Pickl, Winfried F., Akalin, Altuna, Horvat, Filip, Franke, Vedran, Widder, Joachim, Georg, Dietmar, Slade, Dea |
| Předmět: |
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| Zdroj: |
Frontiers in Immunology; 2024, p1-18, 18p |
| Abstrakt: |
Introduction: Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related deaths worldwide with limited treatment options due to extensive radiation and chemotherapy resistance. Monotherapy with immune checkpoint blockade showed no survival benefit. A combination of immunomodulation and radiotherapy may offer new treatment strategies, as demonstrated for non-small cell lung cancer. Radiation-induced anti-tumour immunity is mediated through cytosolic nucleic acid sensing pathways that drive the expression of interferon beta-1 (IFNB1) and proinflammatory cytokines. Methods: Human PDAC cell lines (PANC-1, MIA PaCa-2, BxPC-3) were treated with X-rays and protons. Immunogenic cell death was measured based on HMGB1 release. Cytosolic dsDNA and dsRNA were analysed by immunofluorescence microscopy. Cell cycle progression, MHC-I and PD-L1 expression were determined by flow cytometry. Galectin-1 and IFNB1 were measured by ELISA. The expression levels and the phosphorylation status of the cGAS/STING and RIGI/MAVS signalling pathways were analysed by western blotting, the expression of IFNB1 and proinflammatory cytokines was determined by RT-qPCR and genomewide by RNA-seq. CRISPR-Cas9 knock-outs and inhibitors were used to elucidate the relevance of STING, MAVS and NF-kB for radiation-induced IFNB1 activation. Results: We demonstrate that a clinically relevant X-ray hypofractionation regimen (3x8 Gy) induces immunogenic cell death and activates IFNB1 and proinflammatory cytokines. Fractionated radiation induces G2/M arrest and accumulation of cytosolic DNA in PDAC cells, which partly originates from mitochondria. RNA-seq analysis shows a global upregulation of type I interferon response and NF-kB signalling in PDAC cells following 3x8 Gy. Radiation-induced immunogenic response is regulated by STING, MAVS and NF-kB. In addition to immunostimulation, radiation also induces immunosuppressive galectin-1. No significant changes in MHC-I or PD-L1 expression were observed. Moreover, PDAC cell lines show similar radiationinduced immune effects when exposed to single-dose protons or photons. Conclusion: Our findings provide a rationale for combinatorial radiationimmunomodulatory treatment approaches in PDAC using conventional photon-based or proton beam radiotherapy. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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