liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Semi Mature Blood Dendritic Cells Exist in Patients with Ductal Pancreatic Adenocarcinoma Owing to Inflammatory Factors Released from the Tumor
Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
Show others and affiliations
2010 (English)In: PLOS ONE, ISSN 1932-6203, Vol. 5, no 10Article in journal (Refereed) Published
Abstract [en]

Background: Much evidence exists regarding the fact that blood DCs, both myeloid DCs (MDCs) and plasmacytoid DCs (PDCs), are negatively affected in different types of cancer, with both reduced numbers and impaired functionality. Functional impairment of DCs in patients with pancreatic ductal adenocarcinoma (PDAC), may contribute to the poor clinical outcome. The aim of this study was to examine the effects PDAC had on blood DCs and elucidate the underlying mechanism responsible for the DC impairment. Methodology/Principal Findings: We examined the systemic influence PDAC exerted on blood DCs by ex vivo measuring numerous activation and maturation markers expressed on these cells. Furthermore, the effect patient plasma and the inflammatory factors CXCL8 and PGE(2) had on purified MDCs and PDCs from healthy donors was assessed and compared to the DCs existing in PDAC patients. We found a partial maturation of the blood MDCs and PDCs in PDAC patients with significantly enhanced expression of CD83, CD40, B7H3, PDL-1, CCR6, and CCR7 and decreased expression of ICOSL, and DCIR. These changes lead to impairment in their immunostimulatory function. Furthermore, chronic pancreatitis gave rise to DCs with similar semi-mature phenotype as seen in PDAC. Low expression of ICOSL was associated with poor prognosis. We found that the mechanism underlying this semi-maturation of DCs was inflammatory factors existing in the PDAC patients plasma. Of note, PGE2, which is elevated PDAC patient plasma, was one contributing factor to the changes seen in MDCs and PDCs phenotype. Conclusion/Significance: Our findings point to a role for the systemic inflammation in transforming blood MDCs and PDCs into semi-mature cells in PDAC patients and we show a correlation between maturation status and clinical outcome. Thus, means to preserve a functional blood DC compartment in PDAC patients by diminishing the inflammation could facilitate their ability to control the disease and improve survival.

Place, publisher, year, edition, pages
Public Library of Science (PLoS) , 2010. Vol. 5, no 10
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-61177DOI: 10.1371/journal.pone.0013441ISI: 000283043700026OAI: oai:DiVA.org:liu-61177DiVA: diva2:361041
Note

Original Publication: Vegard Tjomsland, Anna Spångeus, Per Sandström, Kurt Borch, Davorka Messmer and Marie Larsson, Semi Mature Blood Dendritic Cells Exist in Patients with Ductal Pancreatic Adenocarcinoma Owing to Inflammatory Factors Released from the Tumor, 2010, PLOS ONE, (5), 10. http://dx.doi.org/10.1371/journal.pone.0013441 Licensee: Public Library of Science (PLoS) http://www.plos.org/

Available from: 2010-11-08 Created: 2010-11-05 Last updated: 2014-06-04
In thesis
1. Studies of the tumor microenvironment: Local and systemic effects exerted by the cross-talk between tumor and stroma cells in pancreatic cancer
Open this publication in new window or tab >>Studies of the tumor microenvironment: Local and systemic effects exerted by the cross-talk between tumor and stroma cells in pancreatic cancer
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pancreatic cancer is one of the most lethal cancers and despite all research efforts the last 50 years, there are still no effective therapy for this terrible disease. Until quite recently most research in the field of pancreatic duct adenocarcinoma (PDAC) was focused on the tumor cells and mechanisms essential for their proliferation and survival. However, the tumor does not only consist of tumor cells, rather a combination of tumor cells and numerous stroma cell types, i.e. the tumor microenvironment. The tumor cells have developed the ability to activate the surrounding cells to produce factors important for the progression of the tumor. Cancer associated fibroblasts (CAFs) are the major stroma component and as much as 70% of the total PDAC tumor mass consists of these cells. In this thesis I have investigated the mechanisms involved in the cross-talk between tumor cells and CAFs and distinguished the local and systemic effects of this communication. Tumor derived IL-1α was identified as an important factor creating the inflammatory profile seen in CAFs. In PDAC patients, IL-1α was detected in 90% of the tumors and high expression was associated with poor clinical outcome. Moreover, the PDAC tumors had elevated expression levels of many inflammatory factors that were induced in CAFs by the tumor derived IL-1α in vitro. Consequently, this high expression of inflammatory factors in CAFs will attract immune cells including tumor associated macrophages (TAMs), dendritic cells (DCs), and CD8+ T cells. This indicates an immune suppressive role of CAFs, protecting the tumor cells by acting as decoy targets for immune cells homing into the tumor. The inflammatory factors produced in the PDAC microenvironment did not only affect the infiltrating immune cells, but had also systemic effects that included decreased levels of blood DCs in PDAC patients. Furthermore, these myeloid and plasmacytoid DCs were partly activated and had a semi mature phenotype and impaired immunostimulatory function. Low levels of blood DCs were direct associated with poor patient prognosis and the same was seen for low expression of ICOSL by the DCs.

The findings presented in this thesis indicate an essential role for the cross-talk between tumor cells and stroma in the production of tumor  promoting factors. Treatment of PDAC patients with drugs that target the IL-1α signaling pathway could prevent the communication between these cells, thus reduce the amount of inflammatory factors both locally and systemically. Altogether, our findings support the idea that neutralization of the IL-1α signaling molecule could be a promising therapy for pancreatic cancer.

The findings presented in this thesis indicate an essential role for the cross-talk between tumor cells and stroma in the production of tumor promoting factors. Treatment of PDAC patients with drugs that target the IL-1α signaling pathway could prevent the communication between these cells, thus reduce the amount of inflammatory factors both locally and systemically. Altogether, our findings support the idea that neutralization of the IL-1α signaling molecule could be a promising therapy for pancreatic cancer.

Abstract [sv]

Mindre än 5% av patienterna som drabbas av cancer i bukspottkörteln förväntas överleva i mer än fem år. De typiska symtomen kommer sent och sjukdomen framskrider snabbt. Några av de riskfaktorer som identifierats är tobaksrökning, fetma och typ 2 diabetes.

Forskningen har hittills siktat in sig på tumörcellerna och de mekanismer de använder för att överleva och föröka sig. Men en tumör innehåller också normala kroppsceller och vid bukspottkörtelcancer kan så mycket som 70 procent bestå av i sig ofarliga bindvävsceller. Miljön i tumören skapas av samspelet mellan dessa celltyper. De cancerceller som är bäst på att utnyttja omgivningen för sin tillväxt fortlever och för sina egenskaper vidare. En sådan egenskap är att kunna manipulera bindvävsceller till att producera signalsubstanser och tillväxtfaktorer som gynnar tumören.

Mekanismerna bakom denna kommunikation har studerats och ett viktigt fynd var att tumörcellerna producerar signalämnet interleukin 1-alpha (IL-1a). Detta protein upptäcktes i 90 procent av de undersökta tumörerna, och var kopplat till dålig prognos hos patienterna.

Signalen via IL-1a sätter igång tillverkningen av substanser som behövs för nybildning och tillväxt av blodkärl, i sin tur en förutsättning för att tumören ska leva vidare och växa. Proteinet stimulerar också celldelning i tumören, bidrar till att lura kroppens immunförsvar och underlättar spridning av dottertumörer till andra delar av kroppen.

När vi slår ut signaleringen kan tumörcellerna inte längre påverka bindvävscellerna lika effektivt, och således minskar förekomsten av flera faktorer som gynnar tumörtillväxten. IL-1a kan därför vara en lovande kandidat att utforska vidare för framtida som ett läkemedel mot bukspottkörtelcancer.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2010. 69 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1219
Keyword
Pancreatic cancer, cancer associated fibroblasts, dendritic cells, IL-1alpha, tumor microenvironment, inflammation, bukspottkörtelcancer, Bukspyttkjertel kreft
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-67632 (URN)978-91-7393-274-5 (ISBN)
Public defence
2010-12-16, Linden, Hälsouniversitet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2011-04-26 Created: 2011-04-20 Last updated: 2011-04-26Bibliographically approved

Open Access in DiVA

fulltext(2143 kB)227 downloads
File information
File name FULLTEXT01.pdfFile size 2143 kBChecksum SHA-512
53c7474f6b0be3e0e7fae571165b54fad125d30b278e2d31025dbfb35b69901854dcd1a64e44cc83d65459fc22f6e7a62b994d132d04b5e68d4b1a7d332f04ce
Type fulltextMimetype application/pdf

Other links

Publisher's full text

Authority records BETA

Tjomsland, VegardSpångeus, AnnaSandström, PerBorch, KurtLarsson, Marie

Search in DiVA

By author/editor
Tjomsland, VegardSpångeus, AnnaSandström, PerBorch, KurtLarsson, Marie
By organisation
Molecular VirologyFaculty of Health SciencesInternal MedicineSurgeryDepartment of Surgery in Östergötland
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 227 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 157 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf