Combined Flt3L and CD40 agonism restores dendritic cell–driven T cell immunity in pancreatic cancer
T cell-directed immunotherapies have largely failed to slow progression of pancreatic ductal adenocarcinoma (PDAC) because of poor tumor antigenicity and an immunosuppressive tumor microenvironment. We hypothesized that conventional dendritic cell (cDC) suppression in PDAC may further impair tumor immunity. We found that low tissue expression of Fms-like tyrosine kinase 3 ligand (Flt3L) partially underlies cDC deficits. Treatment with systemic Flt3L and CD40 agonists restored cDC number and function in murine models and clinical trial samples from patients with PDAC. CD40 agonism alone did not fully activate cDCs; however, when combined with Flt3L, dual therapy triggered a cDC-driven type I immune response characterized by T cell infiltration, interleukin-12 production, and reciprocal interferon-γ (IFN-γ) responses. In mice, cDC1s were responsible for CD8<sup>+</sup> T cell expansion, and in turn, T cell-derived IFN-γ enhanced cDC1 survival. Nevertheless, Flt3L and CD40 agonism increased regulatory T cells through the activation of cDC2s, dampening immunity. These findings advocate further exploration of DC-centered approaches to enhance antitumor immunity in PDAC.
Authors
- Xiuting Liu (ORCID: https://orcid.org/0000-0003-3791-3885)
- Reyka G. Jayasinghe (ORCID: https://orcid.org/0000-0003-2368-4890)
- Li Ding (ORCID: https://orcid.org/0000-0001-7982-4157)
- Natalie L. Kingston (ORCID: https://orcid.org/0000-0003-0122-907X)
- Liang‐I Kang (ORCID: https://orcid.org/0000-0001-7025-3095)
- Kenneth M. Murphy (ORCID: https://orcid.org/0000-0002-3505-9630)
- John M. Herndon (ORCID: https://orcid.org/0000-0002-8378-9654)
- Varun Shenoy (ORCID: https://orcid.org/0009-0000-9461-1619)
- Roheena Z. Panni (ORCID: https://orcid.org/0000-0002-8144-6869)
- Yu‐Lan Kao (ORCID: https://orcid.org/0000-0003-1229-7502)
- Varintra E. Lander (ORCID: https://orcid.org/0000-0001-8299-7104)
- Graham D. Hogg (ORCID: https://orcid.org/0000-0002-7143-0695)
- William G. Hawkins (ORCID: https://orcid.org/0000-0001-7087-3585)
- Brett L. Knolhoff (ORCID: https://orcid.org/0000-0002-0115-7355)
- Blake E. Sells (ORCID: https://orcid.org/0000-0002-4500-1256)
- David G. DeNardo (ORCID: https://orcid.org/0000-0002-3655-5783)
- Alyssa G. Weinstein (ORCID: https://orcid.org/0000-0001-9342-0263)
- Ryan C. Fields (ORCID: https://orcid.org/0000-0001-6176-8943)
- Andrew Houston (ORCID: https://orcid.org/0000-0002-3837-4695)
- Tiantian Liu (ORCID: https://orcid.org/0000-0001-9377-9938)
- Faiz Ahmad (ORCID: https://orcid.org/0000-0002-0450-042X)
- Olivia M. Dres (ORCID: https://orcid.org/0000-0003-0310-0958)
Institutions
- James S. McDonnell Foundation (US)
- Medical University of South Carolina (US)
- Washington University in St. Louis (US)
- MUSC Hollings Cancer Center (US)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-08-15
- DOI
- https://doi.org/10.1126/sciimmunol.adp3978
- Citations
- 9
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 7.18