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RIG-I agonists promote antigen-spreading and facilitate durable CAR-T responses in pancreatic ductal adenocarcinoma.
J. Immunother. Cancer 14:e013282 (2026)
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains largely refractory to chimeric antigen receptor (CAR)-T cell therapy. Insufficient T cell infiltration, a highly immunosuppressive microenvironment, and antigen loss pose major challenges for CAR-T cell therapy. METHODS: We investigated therapeutic synergies of synthetic 5'-triphosphate RNA (3p-RNA), an agonist of the cytoplasmic double-stranded RNA sensor Retinoic Acid Inducible Gene I (RIG-I), and CAR-T cell therapy using syngeneic and human xenograft PDAC models. Tumor growth, chemokine secretion, immune-cell composition, CAR-T persistence, and endogenous T cell responses were assessed by flow cytometry, multiplex cytokine arrays, Enzyme-linked Immunospot (ELISpot), and vaccination-challenge. RESULTS: 3p-RNA provoked rapid type I interferon accompanied with chemokine ligand CCL5 and CXCL9/10/11 secretion, creating chemokine gradients that recruited chemokine receptor CCR5+/CXCR3+ CAR-T cells into tumors. RIG-I activation enhanced CAR-T cell proliferation, activity, and CAR-T persistence. Combination therapy eradicated established tumors in 60%-70% of mice, whereas either monotherapy was largely ineffective. Cured animals rejected CAR antigen-negative tumor cell rechallenge, demonstrating antigen-spreading and endogenous T cell responses. CONCLUSIONS: Intratumoral RIG-I priming reprograms the PDAC microenvironment, transforming a non-responsive cancer into a CAR-T-permissive one, supporting durable, poly-antigenic immunity. These findings position 3p-RNA as a rapid, clinically tractable co-therapy to extend CAR-T efficacy to solid tumors.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Chimeric Antigen Receptor - Car ; Immunotherapy ; Innate ; Intratumoral ; T Cell; Cancer Cells; Rna; Tumors
ISSN (print) / ISBN
2051-1426
e-ISSN
2051-1426
Quellenangaben
Volume: 14,
Issue: 1,
Article Number: e013282
Publisher
Bmj Publishing Group
Publishing Place
London
Reviewing status
Peer reviewed
Institute(s)
Unit for Clinical Pharmacology (KKG-EKLiP)
Grants
Brigitte and Dr. Konstanze Wegener
Deutsche Forschungsgemeinschaft
Bavarian Cancer Research Center (BZKF)
Fritz-Bender-Stiftung
Else Krner-Fresenius-Stiftung
iTarget 2.0
Bayerische Forschungsstiftung
Deutsche Krebshilfe
Elite Network of Bavaria
Bruno and Helene Jster Foundation
Ernst Jung Stiftung
H2020 European Research Council
odowska-Curie Actions
H2020 Marie Sklstrok
Jos Carreras Leukmie-Stiftung
Monika Kutzner Foundation
Stiftungen zugunsten der Medizinischen Fakultt
Wilhelm Sander-Stiftung
Dr. Rurainski Foundation
Bundesministerium fr Bildung und Forschung
Deutsche Forschungsgemeinschaft
Bavarian Cancer Research Center (BZKF)
Fritz-Bender-Stiftung
Else Krner-Fresenius-Stiftung
iTarget 2.0
Bayerische Forschungsstiftung
Deutsche Krebshilfe
Elite Network of Bavaria
Bruno and Helene Jster Foundation
Ernst Jung Stiftung
H2020 European Research Council
odowska-Curie Actions
H2020 Marie Sklstrok
Jos Carreras Leukmie-Stiftung
Monika Kutzner Foundation
Stiftungen zugunsten der Medizinischen Fakultt
Wilhelm Sander-Stiftung
Dr. Rurainski Foundation
Bundesministerium fr Bildung und Forschung