title: Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma.
abstract: OBJECTIVE
  Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic microenvironment that contains many different immune cells. Activated pancreatic stellate cells (PSCs) contribute to the desmoplasia. We investigated whether distinct stromal compartments are differentially infiltrated by different types of immune cells.
  
  
  METHODS
  We used tissue microarray analysis to compare immune cell infiltration of different pancreaticobiliary diseased tissues (PDAC, ampullary carcinoma, cholangiocarcinoma, mucinous cystic neoplasm, chronic inflammation, and chronic pancreatitis) and juxtatumoral stromal (<100 μm from tumor) and panstromal compartments. We investigated the association between immune infiltrate and patient survival times. We also analyzed T-cell migration and tumor infiltration in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice and the effects of all-trans retinoic acid (ATRA) on these processes.
  
  
  RESULTS
  Juxtatumoral compartments in PDAC samples from 2 independent groups of patients contained increased numbers of myeloperoxidase(+) and CD68(+) cells compared with panstromal compartments. However, juxtatumoral compartments of PDACs contained fewer CD8(+), FoxP3(+), CD56(+), or CD20(+) cells than panstromal compartments, a distinction absent in ampullary carcinomas and cholangiocarcinomas. Patients with PDACs that had high densities of CD8(+) T cells in the juxtatumoral compartment had longer survival times than patients with lower densities. In KPC mice, administration of ATRA, which renders PSCs quiescent, increased numbers of CD8(+) T cells in juxtatumoral compartments. We found that activated PSCs express cytokines, chemokines, and adhesion molecules that regulate T-cell migration. In vitro migration assays showed that CD8(+) T cells, from patients with PDAC, had increased chemotaxis toward activated PSCs, which secrete CXCL12, compared with quiescent PSCs or tumor cells. These effects could be reversed by knockdown of CXCL12 or treatment of PSCs with ATRA.
  
  
  CONCLUSIONS
  Based on studies of human PDAC samples and KPC mice, activated PSCs appear to reduce migration of CD8(+) T cells to juxtatumoral stromal compartments, preventing their access to cancer cells. Deregulated signaling by activated PSCs could prevent an effective antitumor immune response.
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, England.
authors.forename: Abasi
authors.initials: A
authors.lastname: Ene-Obong
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Clear
authors.forename: Jennifer
authors.initials: J
authors.lastname: Watt
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Rewas
authors.initials: R
authors.lastname: Fatah
authors.forename: John C
authors.initials: JC
authors.lastname: Riches
authors.forename: John F
authors.initials: JF
authors.lastname: Marshall
authors.forename: Joanne
authors.initials: J
authors.lastname: Chin-Aleong
authors.forename: Claude
authors.initials: C
authors.lastname: Chelala
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
authors.forename: Alan G
authors.initials: AG
authors.lastname: Ramsay
authors.forename: Hemant M
authors.initials: HM
authors.lastname: Kocher
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D018951:Antigens, CD20 / Q000502:physiology; D019002:CD56 Antigen / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology*; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology* / Q000503:physiopathology; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000502:physiology; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000502:physiology; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D058954:Pancreatic Stellate Cells / Q000473:pathology*
chemical_list: D018951:Antigens, CD20; D019002:CD56 Antigen; D054377:Chemokine CXCL12; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C522918:NCAM1 protein, human
keywords: AC; ATRA; Antitumor Immunity; CC; Immune Regulation; MDSC; Mouse Model; PBD; PDAC; PSC; Pancreatic Cancer; TMA; Treg; aPSC; activated pancreatic stellate cell; all-trans retinoic acid; ampullary carcinoma; cholangiocarcinoma; myeloid-derived suppressor cell; pancreatic ductal adenocarcinoma; pancreatic stellate cell; pancreaticobiliary disease; qPSC; quiescent pancreatic stellate cell; regulatory T cell; tissue microarray
references.citation: Science. 2011 Mar 25;331(6024):1612-6
references.pmid: 21436454
references.citation: Nat Rev Immunol. 2012 Mar 22;12(4):269-81
references.pmid: 22437939
references.citation: Am J Pathol. 2009 Aug;175(2):636-48
references.pmid: 19608876
references.citation: Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5215-20
references.pmid: 10220446
references.citation: J Natl Cancer Inst. 1994 Jun 1;86(11):829-35
references.pmid: 8182763
references.citation: Immunology. 2013 Feb;138(2):105-15
references.pmid: 23216602
references.citation: Cancer Cell. 2012 Jun 12;21(6):836-47
references.pmid: 22698407
references.citation: Clin Cancer Res. 2004 Nov 1;10(21):7252-9
references.pmid: 15534099
references.citation: Cancer Res. 2007 Oct 1;67(19):9518-27
references.pmid: 17909062
references.citation: Am J Pathol. 2002 Apr;160(4):1239-49
references.pmid: 11943709
references.citation: Clin Immunol. 2012 Sep;144(3):250-68
references.pmid: 22858650
references.citation: J Pathol. 2013 May;230(1):107-17
references.pmid: 23359139
references.citation: J Exp Med. 1996 Sep 1;184(3):1101-9
references.pmid: 9064327
references.citation: J Biol Chem. 2012 Nov 9;287(46):39115-24
references.pmid: 22995914
references.citation: Blood. 2013 Feb 28;121(9):1612-21
references.pmid: 23247726
references.citation: Science. 2011 Mar 25;331(6024):1565-70
references.pmid: 21436444
references.citation: Int J Surg Pathol. 2013 Apr;21(2):111-20
references.pmid: 22649166
references.citation: Cancer Epidemiol. 2012 Aug;36(4):e207-14
references.pmid: 22534487
references.citation: N Engl J Med. 2003 Jan 16;348(3):203-13
references.pmid: 12529460
references.citation: Nature. 2012 Feb 08;482(7385):400-4
references.pmid: 22318521
references.citation: Science. 2006 Sep 29;313(5795):1960-4
references.pmid: 17008531
references.citation: Gastroenterology. 2012 May;142(5):1079-92
references.pmid: 22406637
references.citation: Science. 2009 Jun 12;324(5933):1457-61
references.pmid: 19460966
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Nat Rev Immunol. 2011 Feb;11(2):119-30
references.pmid: 21267013
references.citation: Gastroenterology. 2011 Oct;141(4):1486-97, 1497.e1-14
references.pmid: 21704588
references.citation: Cancer Cell. 2012 Jun 12;21(6):822-35
references.pmid: 22698406
references.citation: Am J Pathol. 2002 Jan;160(1):91-9
references.pmid: 11786403
references.citation: Cancer Biol Ther. 2005 Mar;4(3):302-7
references.pmid: 15876873
references.citation: J Natl Cancer Inst. 2007 Aug 1;99(15):1188-99
references.pmid: 17652277
references.citation: Annu Rev Immunol. 2011;29:235-71
references.pmid: 21219185
references.citation: Cell Cycle. 2012 Apr 1;11(7):1282-90
references.pmid: 22421149
references.citation: Cancer Res. 2013 May 15;73(10):3007-18
references.pmid: 23514705
references.citation: J Clin Oncol. 2006 Nov 1;24(31):5052-9
references.pmid: 17033038
references.citation: Science. 2010 Nov 5;330(6005):827-30
references.pmid: 21051638
references.citation: Gastroenterology. 2013 Jun;144(6):1210-9
references.pmid: 23622130
references.citation: Gut. 2011 Jun;60(6):861-8
references.pmid: 20966025