Using a genetically engineered mouse model of pancreatic cancer, Lin et al. showed that cDC1s, but not their precursors, were systemically reduced and not fully matured, and CD8+ T cell priming was impaired. RNAseq of cDC1s showed apoptotic gene enrichment and blunted induction of genes for T cell-polarizing cytokines. In vivo, anti-IL-6 neutralized cDC1 apoptosis, and cDC1 maturation/function was rescued by CD40 agonism, which synergized with Flt3 to restore cDC1 numbers and CD8+ T cell responses to control KPC tumor outgrowth. Peripheral blood cDC1s were reduced in patients with advanced pancreatic cancer, and intratumoral cDC1 levels/maturation correlated with cytolytic activity.
Contributed by Paula Hochman
ABSTRACT: Type 1 conventional dendritic cells (cDC1s) are typically thought to be dysregulated secondarily to invasive cancer. Here, we report that cDC1 dysfunction instead develops in the earliest stages of preinvasive pancreatic intraepithelial neoplasia (PanIN) in the KrasLSL-G12D/+ Trp53LSL-R172H/+ Pdx1-Cre-driven (KPC) mouse model of pancreatic cancer. cDC1 dysfunction is systemic and progressive, driven by increased apoptosis, and results in suboptimal up-regulation of T cell-polarizing cytokines during cDC1 maturation. The underlying mechanism is linked to elevated IL-6 concomitant with neoplasia. Neutralization of IL-6 in vivo ameliorates cDC1 apoptosis, rescuing cDC1 abundance in tumor-bearing mice. CD8+ T cell response to vaccination is impaired as a result of cDC1 dysregulation. Yet, combination therapy with CD40 agonist and Flt3 ligand restores cDC1 abundance to normal levels, decreases cDC1 apoptosis, and repairs cDC1 maturation to drive superior control of tumor outgrowth. Our study therefore reveals the unexpectedly early and systemic onset of cDC1 dysregulation during pancreatic carcinogenesis and suggests therapeutically tractable strategies toward cDC1 repair.