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Prognostic impact of tumour-infiltrating lymphocytes and cancer-associated fibroblasts in patients with pancreatic adenocarcinoma of the body and tail undergoing resection.

Published on May 1, 2020in British Journal of Surgery5.572
· DOI :10.1002/BJS.11434
T. Delayre1
Estimated H-index: 1
(AMU: Aix-Marseille University),
Théophile Guilbaud4
Estimated H-index: 4
(AMU: Aix-Marseille University)
+ 7 AuthorsDaniel Birnbaum35
Estimated H-index: 35
(AMU: Aix-Marseille University)
Abstract
BACKGROUND: The prognosis of patients with pancreatic cancer remains poor and novel therapeutic targets are required urgently. Treatment resistance could be due to the tumour microenvironment, a desmoplastic stroma consisting of cancer-associated fibroblasts and tumour-infiltrating lymphocytes (TILs). The aim of the study was to evaluate the prognostic value of TILs and cancer-associated fibroblasts (CAFs) in pancreatic cancer of the body and tail. METHODS: Using tissue microarray from resected left-sided pancreatic cancer specimens, the immunohistochemistry of TILs (cluster of differentiation (CD) 45, CD3, CD4, FoxP3 and CD8), CAFs (vimentin and alpha-smooth muscle actin (alphaSMA)) and functional markers (PD-L1 and Ki-67) was examined, and the association with disease-free (DFS) and overall (OS) survival investigated using a computer-assisted quantitative analysis. Patients were classified into two groups, with low or high levels or ratios, using the 75th percentile value as the cut-off. RESULTS: Forty-three patients were included in the study. Their median DFS and OS were 9 and 27 months respectively. A high CD4/CD3 lymphocyte ratio was associated with poorer DFS (8 months versus 11 months for a low ratio) (hazard ratio (HR) 2.23, 95 per cent c.i. 1.04 to 4.61; P = 0.041) and OS (13 versus 27 months respectively) (HR 2.62, 1.11 to 5.88; P = 0.028). A low alphaSMA/vimentin ratio together with a high CD4/CD3 ratio was correlated with poorer outcomes. No significant association was found between Ki-67, PD-L1 and survival. CONCLUSION: In patients with resected left-sided pancreatic cancer, a tumour microenvironment characterized by a high CD4/CD3 lymphocyte ratio along with a low alphaSMA/vimentin ratio is correlated with poorer survival.
  • References (36)
  • Citations (1)
References36
Newest
#1Cindy NeuzilletH-Index: 17
Last. HemantMKocher (QMUL: Queen Mary University of London)
view all 18 authors...
This is the peer reviewed version of the following article: Neuzillet, C., et al. (2019). "Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma." The Journal of Pathology 248(1): 51-65., which has been published in final form at https://doi.org/10.1002/path.5224. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
27 CitationsSource
#1David J. BirnbaumH-Index: 9
#1David Jérémie Birnbaum (AMU: Aix-Marseille University)H-Index: 12
Last. Emilie Mamessier (AMU: Aix-Marseille University)H-Index: 23
view all 5 authors...
The association between pancreatic ductal adenocarcinoma (PDAC) location (head vs. Body/Tail (B/T)) and clinical outcome remains controversial. We collected clinicopathological and gene expression data from 249 resected PDAC samples from public data sets, and we compared data between 208 head and 41 B/T samples. The 2-year overall survival (OS) was better for the head than for the B/T PDACs (44 vs. 27%, p = 0.043), especially when comparing tumors with similar TNM classification (T3/4N0M0: 67% v...
13 CitationsSource
#1Thierry ConroyH-Index: 47
#2Pascal HammelH-Index: 58
Last. Jean-Baptiste Bachet (University of Lorraine)H-Index: 1
view all 32 authors...
Abstract Background Among patients with metastatic pancreatic cancer, combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall surviv...
284 CitationsSource
#1Ujjwal M. Mahajan (LMU: Ludwig Maximilian University of Munich)H-Index: 8
#2Eno LanghoffH-Index: 1
Last. Julia Mayerle (LMU: Ludwig Maximilian University of Munich)H-Index: 17
view all 29 authors...
Background & Aims Changes to the microenvironment of pancreatic ductal adenocarcinomas (PDACs) have been associated with poor outcomes of patients. We studied the associations between composition of the pancreatic stroma (fibrogenic, inert, dormant, or fibrolytic stroma) and infiltration by inflammatory cells and times of progression-free survival (PFS) of patients with PDACs after resection. Methods We obtained 1824 tissue microarray specimens from 385 patients included in the European Study Gr...
37 CitationsSource
#1Ana Costa (French Institute of Health and Medical Research)H-Index: 5
#2Yann Kieffer (French Institute of Health and Medical Research)H-Index: 8
Last. Fatima Mechta-Grigoriou (French Institute of Health and Medical Research)H-Index: 24
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Summary Carcinoma-associated fibroblasts (CAF) are key players in the tumor microenvironment. Here, we characterize four CAF subsets in breast cancer with distinct properties and levels of activation. Two myofibroblastic subsets (CAF-S1, CAF-S4) accumulate differentially in triple-negative breast cancers (TNBC). CAF-S1 fibroblasts promote an immunosuppressive environment through a multi-step mechanism. By secreting CXCL12, CAF-S1 attracts CD4 + CD25 + T lymphocytes and retains them by OX40L, PD-...
201 CitationsSource
#1Stephan Dreyer (Glas.: University of Glasgow)H-Index: 4
#2Nigel B. Jamieson (Glas.: University of Glasgow)H-Index: 34
Last. David K. Chang (Glas.: University of Glasgow)H-Index: 40
view all 7 authors...
Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease, with very little improvement in survival over the past 50 years. Recent large-scale genomic studies have improved understanding of the genomic and transcriptomic landscape of the disease, yet very little is known about molecular heterogeneity according to tumour location in the pancreas; body and tail PDACs especially tend to have a significantly worse prognosis. The aim was to investigate the molecular differences between PDAC of...
31 CitationsSource
#1Reza Nejati (University of Texas MD Anderson Cancer Center)H-Index: 2
Last. Huamin Wang (University of Texas MD Anderson Cancer Center)H-Index: 63
view all 16 authors...
Objectives The aim of this study was to examine tumor-infiltrating lymphocytes (TILs) and their prognostic value in patients with pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy. Methods Intratumoral CD4+, CD8+, and FOXP3+ lymphocytes were examined by immunohistochemistry using a computer-assisted quantitative analysis in 136 PDAC patients who received neoadjuvant therapy and pancreaticoduodenectomy. The results were correlated with clinicopathological parameters and survival. ...
12 CitationsSource
#1Daniel Öhlund (Umeå University)H-Index: 9
#2Abram Handly-Santana (CSHL: Cold Spring Harbor Laboratory)H-Index: 2
Last. David A. Tuveson (CSHL: Cold Spring Harbor Laboratory)H-Index: 75
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Pancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that produce desmoplastic stroma, thereby modulating disease progression and therapeutic response in pancreatic ductal adenocarcinoma (PDA). However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of CAFs with distinct phenotypes in PDA exist. We identified a CAF subpopulation with elevated expression of α-smooth muscle actin (αSMA) located immediately adjacent to neoplastic cells ...
358 CitationsSource
#1Ho Kyoung Hwang (Yonsei University)H-Index: 19
#2Hugh Chul Kim (Yonsei University)H-Index: 16
Last. Woo Jung Lee (Yonsei University)H-Index: 38
view all 7 authors...
: Among the subsets of tumor-infiltrating lymphocytes (TILs), activated cytotoxic T lymphocytes (granzyme B+) have an antitumor effect, while regulatory T lymphocytes [forkhead box P3 (Foxp3)+] suppress the antitumor immune response. The aim of the present study was to investigate the possible associations between TIL subsets and survival outcomes in patients with left-sided pancreatic ductal adenocarcinoma (PDAC). From January 2000 to December 2008, 30 patients who underwent curative distal pan...
10 CitationsSource
#1David Jérémie Birnbaum (AMU: Aix-Marseille University)H-Index: 12
#1David J. BirnbaumH-Index: 9
Last. François BertucciH-Index: 53
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// David J. Birnbaum 1,2,3 , Pascal Finetti 1 , Alexia Lopresti 1 , Marine Gilabert 4,5 , Flora Poizat 4,7 , Olivier Turrini 3,4,6 , Jean-Luc Raoul 4,5 , Jean-Robert Delpero 3,4,6 , Vincent Moutardier 2 , Daniel Birnbaum 1,3 , Emilie Mamessier 1,4,* and Francois Bertucci 1,3,4,5,* 1 Departement d’Oncologie Moleculaire, Centre de Recherche en Cancerologie de Marseille, INSERM, CNRS, Universite Aix-Marseille, Marseille, France 2 Departement de Chirurgie Generale et Viscerale, AP-HM, Marseille, Fra...
37 CitationsSource
Cited By1
Newest
#1Louisa BolmH-Index: 6
Last. Tobias KeckH-Index: 33
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Introduction The aim of this study was to define histo-morphological stroma characteristics by analyzing stromal components, and to evaluate their impact on local and systemic tumor spread and overall survival in pancreatic ductal adenocarcinoma (PDAC). Methods and materials Patients who underwent oncologic resections with curative intent for PDAC were identified from a prospectively maintained database. Histological specimens were re-evaluated for morphological stroma features as stromal fibers...
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