Abstract B31: Type 1 conventional dendritic cells are progressively and systemically dysregulated early in pancreatic carcinogenesis

Dendritic cell (DC) dysregulation in cancer has long been hypothesized to be a tumor-associated phenomenon. Using the KPC autochthonous mouse model of pancreatic ductal adenocarcinoma, we reveal that dysfunction of type 1 conventional DCs (cDC1s)—critical mediators of antitumor T-cell immunity—instead develops in the preinvasive stage of carcinogenesis and impacts the host systemically prior to malignancy. Both cDC1 survival and function are impacted, with cDC1s suspended in a state of semi-maturation in which genes involved in response to inflammation and proteasomal degradation are successfully upregulated while genes encoding T cell-polarizing cytokines necessary for T-cell activation fail to be induced. cDC1 dysfunction subsequently impairs CD8+ T-cell activation in vivo. However, this defect remains reversible even following progression to invasive cancer. CD40 activation induces an IFNg response signature that drives cDC1 maturation and migration to draining lymph nodes, restoring CD8+ T-cell activation to normal levels. This study therefore reveals the unexpected depths of cDC1 dysregulation in carcinogenesis but nevertheless elaborates therapeutically tractable strategies towards cDC1 repair. Citation Format: Jeffrey H. Lin, Austin P. Huffman, Emma E. Furth, Robert H. Vonderheide. Type 1 conventional dendritic cells are progressively and systemically dysregulated early in pancreatic carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B31.