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

Sebastian Lundgren, Emelie Karnevi, Jacob Elebro, Björn Nodin, Mikael C I Karlsson, Jakob Eberhard, Karin Leandersson, Karin Jirström, Sebastian Lundgren, Emelie Karnevi, Jacob Elebro, Björn Nodin, Mikael C I Karlsson, Jakob Eberhard, Karin Leandersson, Karin Jirström

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 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.

Figures

Fig. 1
Fig. 1
Sample immunohistochemical images. Sample images of immunohistochemical staining of CD1a+ TIDC in a PB-type, b I-type tumour, CD68+ TAM in c PB-type, d I-type tumour, CD163+ TAM in e PB-type, f I-type tumour, and MARCO+ TAM in g PB-type, h I-type. Scale bar represents 20 μm
Fig. 2
Fig. 2
Kaplan–Meier estimates of survival according to CD1a+ TIDC density. Kaplan–Meier estimates of 5-year overall survival according to high and low TIDCs density in a the entire cohort, b in I-type tumours and c in PB-type tumours
Fig. 3
Fig. 3
Kaplan–Meier estimates of survival according to CD68+ TAM density. Kaplan–Meier estimates of 5-year overall survival according to high and low CD68+ TAM density in a the entire cohort, b in I-type tumours and c in PB-type tumours
Fig. 4
Fig. 4
Kaplan–Meier estimates of survival according to CD163+ TAM density. Kaplan–Meier estimates of 5-year overall survival according to high and low CD163+ TAM density in a the entire cohort, b in I-type tumours and c in PB-type tumours
Fig. 5
Fig. 5
Kaplan–Meier estimates of survival according to MARCO+ TAM density. Kaplan–Meier estimates of 5-year overall survival according to high and low MARCO+ TAM density in a the entire cohort, b in I-type tumours and c in PB-type tumours
Fig. 6
Fig. 6
Kaplan–Meier estimates of survival according to MARCO+ TAM density and adjuvant chemotherapy. Kaplan–Meier estimates of 5-year overall survival according to high and low MARCO+ TAM density in patients with I-type tumours a not treated with adjuvant chemotherapy and b treated with adjuvant chemotherapy

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Source: PubMed

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