Combined Flt3L and CD40 agonism restores dendritic cell driven T cell immunity in mouse models and patients with pancreatic cancer [mouse]

ABSTRACT: T cell directed immunotherapies have largely failed to demonstrate clinical efficacy in patients with pancreatic ductal adenocarcinoma (PDAC). This broad resistance may result from poor tumor antigenicity and an immunosuppressive tumor microenvironment (TME). We hypothesize that tumor immunity in pancreatic cancer patients is further limited by systemic and tumor-intrinsic suppression of conventional dendritic cells (cDC). Here, we find that low tissue expression of Flt3L may in part underly cDC deficits in PDAC tissues. We show in both autochthonous murine models and samples from a clinical trial, that treatment with systemic Flt3L and CD40 agonists can restore cDC number and function in the PDAC TME. Alone, CD40 agonism failed to fully engage cDC activity; yet when combined with Flt3L, the dual therapy triggered a cDC driven type-I immune response characterized by CD8+ T cell infiltration, interleukin-12 production, and a reciprocal interferon (IFN) response. In mice, type-1 cDCs (cDC1) were directly responsible for the influx of CD8+ T cells, which in-turn supported cDC1 survival via IFN-γ, resulting in a synergistic feed-forward loop. Lastly, while we find that combination Flt3L and CD40 agonism improve tumor immunity, they also increase the number and effector phenotype of FOXP3+ regulatory T cells (Tregs) in a process dependent on type-2 cDCs. Tregs were found to limit therapeutic efficacy by inhibiting mature cDC subsets, and concurrent Treg depletion led to improved tumor control. These data support the continued investigation of combined Flt3L and CD40. agonism, which represent a promising strategy to engage anti-tumor immunity in advanced human malignancies.

ORGANISM(S): Mus musculus

PROVIDER: GSE283198 | GEO | 2025/06/20

REPOSITORIES: GEO