Dendritic Cell Paucity Leads to Dysfunctional Immune Surveillance in Pancreatic Cancer

• DOI: 10.1016/j.ccell.2020.02.008
• Publication Date: 2020-03-16T18:09:16Z
• Authors: Samarth Hegde; Varintra E. Krisn...; Brett H. Herzog; Chong Zuo; Marcus A. Breden; Brett L. Knolhoff; Graham D. Hogg; Jack P. Tang; John M. Baer; Cedric Mpoy; Kyung Bae Lee; Katherine A. Alex...; Buck E. Rogers; Kenneth M. Murphy; William G. Hawkins; Ryan C. Fields; Carl J. DeSelm; Julie K. Schwarz; David G. DeNardo
• Keywords: CD4-Positive T-Lymphocytes; Lung Neoplasms; Adenocarcinoma of Lung; Mice, Transgenic; Dendritic Cells; CD8-Positive T-Lymphocytes; Mice, Mutant Strains; 3. Good health; Mice, Inbred C57BL; Pancreatic Neoplasms; Mice; Cell Line, Tumor; Animals; Humans; Immunotherapy; Carcinoma, Pancreatic Ductal

Here, we utilized spontaneous models of pancreatic and lung cancer to examine how neoantigenicity shapes tumor immunity and progression. As expected, neoantigen expression during lung adenocarcinoma development leads to T cell-mediated immunity and disease restraint. By contrast, neoantigen expression in pancreatic ductal adenocarcinoma (PDAC) results in exacerbation of a fibro-inflammatory microenvironment that drives disease progression and metastasis. Pathogenic TH17 responses are responsible for this neoantigen-induced tumor progression in PDAC. Underlying these divergent T cell responses in pancreas and lung cancer are differences in infiltrating conventional dendritic cells (cDCs). Overcoming cDC deficiency in early-stage PDAC leads to disease restraint, while restoration of cDC function in advanced PDAC restores tumor-restraining immunity and enhances responsiveness to radiation therapy.