Hegde et al. created autochthonous pancreatic (PDAC) and lung (LAC) adenocarcinoma mouse models with a regulatable, traceable tumor neoantigen (Ag). In contrast to Ag+ LAC, in Ag+ PDAC tumor progression escalated, Ag persisted, and infiltrating TH17 CD4+ and PD1hiTIM3hi CD8+ T cells (vs TH1 for Ag+ LAC) increased; fewer cDC1s (which were immature) were observed. Flt3 DC precursor mobilization with CD40 and/or STING agonism restored cDC1 levels as well as TH1 and CD8+ T cell Ag responses in early PDAC, and synergized with radiation therapy in late PDAC to reduce tumor growth. cDC1s were rare in human PDAC vs LAC.
Contributed by Paula Hochman
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.
Author Info: (1) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (2) Department of Medicine, Washington University School of Medicine, St. Louis, MO
Author Info: (1) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (2) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (3) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (4) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (5) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (6) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (7) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (8) Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA. (9) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (10) Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA. (11) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (12) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (13) 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. (14) 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. (15) Department of Surgery, Barnes-Jewish Hospital, St. Louis, MO 63110, USA; Alvin J. Siteman Comprehensive Cancer Center, St. Louis, MO 63110, USA. (16) Department of Surgery, Barnes-Jewish Hospital, St. Louis, MO 63110, USA; Alvin J. Siteman Comprehensive Cancer Center, St. Louis, MO 63110, USA. (17) 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. (18) 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. (19) 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.
