1. Academic Validation
  2. Dendritic Cell Paucity Leads to Dysfunctional Immune Surveillance in Pancreatic Cancer

Dendritic Cell Paucity Leads to Dysfunctional Immune Surveillance in Pancreatic Cancer

  • Cancer Cell. 2020 Mar 16;37(3):289-307.e9. doi: 10.1016/j.ccell.2020.02.008.
Samarth Hegde 1 Varintra E Krisnawan 1 Brett H Herzog 1 Chong Zuo 1 Marcus A Breden 1 Brett L Knolhoff 1 Graham D Hogg 1 Jack P Tang 2 John M Baer 1 Cedric Mpoy 2 Kyung Bae Lee 1 Katherine A Alexander 1 Buck E Rogers 3 Kenneth M Murphy 4 William G Hawkins 5 Ryan C Fields 5 Carl J DeSelm 3 Julie K Schwarz 6 David G DeNardo 7
Affiliations

Affiliations

  • 1 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 2 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 3 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA; Alvin J. Siteman Comprehensive Cancer Center, St. Louis, MO 63110, USA.
  • 4 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 5 Department of Surgery, Barnes-Jewish Hospital, St. Louis, MO 63110, USA; Alvin J. Siteman Comprehensive Cancer Center, St. Louis, MO 63110, USA.
  • 6 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA; Alvin J. Siteman Comprehensive Cancer Center, St. Louis, MO 63110, USA.
  • 7 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Alvin J. Siteman Comprehensive Cancer Center, St. Louis, MO 63110, USA. Electronic address: ddenardo@wustl.edu.
Abstract

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.

Keywords

CD40; Flt3L; dendritic cell; immune surveillance; immunotherapy; neoantigen; pancreatic cancer; radiation therapy; vaccination.

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