title: Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer.
abstract: Pancreatic cancer is characterised by the accumulation of a fibro-inflammatory stroma. Within this stromal reaction, myeloid cells are a predominant population. Distinct myeloid subsets have been correlated with tumour promotion and unmasking of anti-tumour immunity.
  
  
  
  The goal of this study was to determine the effect of myeloid cell depletion on the onset and progression of pancreatic cancer and to understand the relationship between myeloid cells and T cell-mediated immunity within the pancreatic cancer microenvironment.
  
  
  
  Primary mouse pancreatic cancer cells were transplanted into CD11b-diphtheria toxin receptor (DTR) mice. Alternatively, the iKras* mouse model of pancreatic cancer was crossed into CD11b-DTR mice. CD11b+cells (mostly myeloid cell population) were depleted by diphtheria toxin treatment during tumour initiation or in established tumours.
  
  
  
  Depletion of myeloid cells prevented KrasG12D-driven pancreatic cancer initiation. In pre-established tumours, myeloid cell depletion arrested tumour growth and in some cases, induced tumour regressions that were dependent on CD8+T cells. We found that myeloid cells inhibited CD8+T-cell anti-tumour activity by inducing the expression of programmed cell death-ligand 1 (PD-L1) in tumour cells in an epidermal growth factor receptor (EGFR)/mitogen-activated protein kinases (MAPK)-dependent manner.
  
  
  
  Our results show that myeloid cells support immune evasion in pancreatic cancer through EGFR/MAPK-dependent regulation of PD-L1 expression on tumour cells. Derailing this crosstalk between myeloid cells and tumour cells is sufficient to restore anti-tumour immunity mediated by CD8+T cells, a finding with implications for the design of immune therapies for pancreatic cancer.
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Velez-Delgado
authors.affiliation: Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Esha
authors.initials: E
authors.lastname: Mathew
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.|Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Dongjun
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Flor M
authors.initials: FM
authors.lastname: Mendez
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Flannagan
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.|Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rhim
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.|Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Simeone
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.|Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Beatty
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.|Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.|Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, USA.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Pasca di Magliano
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism*; D039481:CD11b Antigen / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007111:Immunity, Cellular; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D022423:Myeloid Cells / Q000737:chemistry / Q000276:immunology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D019139:Tumor Escape; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; D039481:CD11b Antigen; C498919:Cd274 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: GENE REGULATION; IMMUNE RESPONSE; MACROPHAGES; PANCREATIC CANCER; SIGNAL TRANSDUCTION