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
  • 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: [email protected].
PMID: 32183949 DOI: 10.1016/j.ccell.2020.02.008
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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