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The clinical importance of tumour-infiltrating macrophages and dendritic cells in periampullary adenocarcinoma differs by morphological subtype

Lundgren, Sebastian LU ; Karnevi, Emelie LU ; Elebro, Jacob LU ; Nodin, Björn LU ; Karlsson, Mikael C.I.; Eberhard, Jakob LU ; Leandersson, Karin LU and Jirström, Karin LU (2017) In Journal of Translational Medicine 15(1).
Abstract

Background: Dendritic cells (DC) and tumour-associated macrophages (TAM) are essential in linking the innate and adaptive immune response against tumour cells and tumour progression. These cells are also potential target for immunotherapy as well as providing a handle to investigate immune status in the tumour microenvironment. The aim of the present study was to examine their impact on prognosis and chemotherapy response in periampullary adenocarcinoma, including pancreatic cancer, with particular reference to morphological subtype. Methods: The density of tolerogenic immature CD1a+ dendritic cells (DC), and MARCO+, CD68+ and CD163+ tissue-associated macrophages (TAM) was analysed by... (More)

Background: Dendritic cells (DC) and tumour-associated macrophages (TAM) are essential in linking the innate and adaptive immune response against tumour cells and tumour progression. These cells are also potential target for immunotherapy as well as providing a handle to investigate immune status in the tumour microenvironment. The aim of the present study was to examine their impact on prognosis and chemotherapy response in periampullary adenocarcinoma, including pancreatic cancer, with particular reference to morphological subtype. Methods: The density of tolerogenic immature CD1a+ dendritic cells (DC), and MARCO+, CD68+ and CD163+ tissue-associated macrophages (TAM) was analysed by immunohistochemistry in tissue micro arrays with tumours from 175 consecutive cases of periampullary adenocarcinoma who had undergone pancreaticoduodenectomy, 110 with pancreatobiliary type (PB-type) and 65 with intestinal type (I-type) morphology. Kaplan-Meier and Cox regression analyses were applied to determine the impact of immune cell infiltration on 5-year overall survival (OS). Results: High density of CD1a+ DCs was an independent prognostic factor for a reduced OS in PB-type but not in I-type tumours (adjusted HR = 2.35; 95% CI 1.13-4.87). High density of CD68+ and CD163+ TAM was significantly associated with poor OS in the whole cohort, however only in unadjusted analysis (HR = 1.67; 95% CI 1.06-2.63, and HR = 1.84; 95% CI 1.09-3.09, respectively) and not in strata according to morphological subtype. High density of MARCO+ macrophages was significantly associated with poor prognosis in I-type but not in PB-type tumours (HR = 2.14 95% CI 1.03-4.44), and this association was only evident in patients treated with adjuvant chemotherapy. The prognostic value of the other investigated immune cells did not differ significantly in strata according to adjuvant chemotherapy. Conclusions: The results from this study demonstrate that high infiltration of tolerogenic immature DCs independently predicts a shorter survival in patients with PB-type periampullary adenocarcinoma, and that high density of the MARCO+ subtype of TAMs predicts a shorter survival in patients with I-type tumours. These results emphasise the importance of taking morphological subtype into account in biomarker studies related to periampullary cancer, and indicate that therapies targeting dendritic cells may be of value in the treatment of PB-type tumours, which are associated with the worst prognosis.

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author
organization
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type
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publication status
published
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in
Journal of Translational Medicine
volume
15
issue
1
publisher
BioMed Central
external identifiers
  • scopus:85021676337
  • wos:000405770300001
ISSN
1479-5876
DOI
10.1186/s12967-017-1256-y
language
English
LU publication?
yes
id
7d4eeef6-5d4d-4877-8fb6-1b1099c0b9d2
alternative location
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496326/
date added to LUP
2017-07-26 08:44:00
date last changed
2017-09-18 11:39:33
@article{7d4eeef6-5d4d-4877-8fb6-1b1099c0b9d2,
  abstract     = {<p>Background: Dendritic cells (DC) and tumour-associated macrophages (TAM) are essential in linking the innate and adaptive immune response against tumour cells and tumour progression. These cells are also potential target for immunotherapy as well as providing a handle to investigate immune status in the tumour microenvironment. The aim of the present study was to examine their impact on prognosis and chemotherapy response in periampullary adenocarcinoma, including pancreatic cancer, with particular reference to morphological subtype. Methods: The density of tolerogenic immature CD1a<sup>+</sup> dendritic cells (DC), and MARCO<sup>+</sup>, CD68<sup>+</sup> and CD163<sup>+</sup> tissue-associated macrophages (TAM) was analysed by immunohistochemistry in tissue micro arrays with tumours from 175 consecutive cases of periampullary adenocarcinoma who had undergone pancreaticoduodenectomy, 110 with pancreatobiliary type (PB-type) and 65 with intestinal type (I-type) morphology. Kaplan-Meier and Cox regression analyses were applied to determine the impact of immune cell infiltration on 5-year overall survival (OS). Results: High density of CD1a<sup>+</sup> DCs was an independent prognostic factor for a reduced OS in PB-type but not in I-type tumours (adjusted HR = 2.35; 95% CI 1.13-4.87). High density of CD68<sup>+</sup> and CD163<sup>+</sup> TAM was significantly associated with poor OS in the whole cohort, however only in unadjusted analysis (HR = 1.67; 95% CI 1.06-2.63, and HR = 1.84; 95% CI 1.09-3.09, respectively) and not in strata according to morphological subtype. High density of MARCO<sup>+</sup> macrophages was significantly associated with poor prognosis in I-type but not in PB-type tumours (HR = 2.14 95% CI 1.03-4.44), and this association was only evident in patients treated with adjuvant chemotherapy. The prognostic value of the other investigated immune cells did not differ significantly in strata according to adjuvant chemotherapy. Conclusions: The results from this study demonstrate that high infiltration of tolerogenic immature DCs independently predicts a shorter survival in patients with PB-type periampullary adenocarcinoma, and that high density of the MARCO<sup>+</sup> subtype of TAMs predicts a shorter survival in patients with I-type tumours. These results emphasise the importance of taking morphological subtype into account in biomarker studies related to periampullary cancer, and indicate that therapies targeting dendritic cells may be of value in the treatment of PB-type tumours, which are associated with the worst prognosis.</p>},
  articleno    = {152},
  author       = {Lundgren, Sebastian and Karnevi, Emelie and Elebro, Jacob and Nodin, Björn and Karlsson, Mikael C.I. and Eberhard, Jakob and Leandersson, Karin and Jirström, Karin},
  issn         = {1479-5876},
  language     = {eng},
  month        = {07},
  number       = {1},
  publisher    = {BioMed Central},
  series       = {Journal of Translational Medicine},
  title        = {The clinical importance of tumour-infiltrating macrophages and dendritic cells in periampullary adenocarcinoma differs by morphological subtype},
  url          = {http://dx.doi.org/10.1186/s12967-017-1256-y},
  volume       = {15},
  year         = {2017},
}