title: Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity.
abstract: BACKGROUND
  Pancreatic ductal adenocarcinoma (PDA) is characterised by a robust desmoplasia, including the notable accumulation of immunosuppressive cells that shield neoplastic cells from immune detection. Immune evasion may be further enhanced if the malignant cells fail to express high levels of antigens that are sufficiently immunogenic to engender an effector T cell response.
  
  
  OBJECTIVE
  To investigate the predominant subsets of immunosuppressive cancer-conditioned myeloid cells that chronicle and shape the progression of pancreas cancer. We show that selective depletion of one subset of myeloid-derived suppressor cells (MDSC) in an autochthonous, genetically engineered mouse model (GEMM) of PDA unmasks the ability of the adaptive immune response to engage and target tumour epithelial cells.
  
  
  METHODS
  A combination of in vivo and in vitro studies were performed employing a GEMM that faithfully recapitulates the cardinal features of human PDA. The predominant cancer-conditioned myeloid cell subpopulation was specifically targeted in vivo and the biological outcomes determined.
  
  
  RESULTS
  PDA orchestrates the induction of distinct subsets of cancer-associated myeloid cells through the production of factors known to influence myelopoiesis. These immature myeloid cells inhibit the proliferation and induce apoptosis of activated T cells. Targeted depletion of granulocytic MDSC (Gr-MDSC) in autochthonous PDA increases the intratumoral accumulation of activated CD8 T cells and apoptosis of tumour epithelial cells and also remodels the tumour stroma.
  
  
  CONCLUSIONS
  Neoplastic ductal cells of the pancreas induce distinct myeloid cell subsets that promote tumour cell survival and accumulation. Targeted depletion of a single myeloid subset, the Gr-MDSC, can unmask an endogenous T cell response, disclosing an unexpected latent immunity and invoking targeting of Gr-MDSC as a potential strategy to exploit for treating this highly lethal disease.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA Department of Immunology, University of Washington, Seattle, Washington, USA.
authors.forename: Ingunn M
authors.initials: IM
authors.lastname: Stromnes
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Brockenbrough
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Kamel
authors.identifier: http://orcid.org/0000-0003-4061-4886
authors.initials: K
authors.lastname: Izeradjene
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Carlson
authors.affiliation: Department of Radiology, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cuevas
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Randi M
authors.initials: RM
authors.lastname: Simmons
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA Department of Immunology, University of Washington, Seattle, Washington, USA Division of Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Greenberg
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA Division of Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Hingorani
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005818:Genetic Engineering; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D038042:Myelopoiesis / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000473:pathology; D013154:Spleen / Q000276:immunology
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Growth Factors; Immune Response; Pancreatic Cancer