Abstract
Chemokines play essential roles in the progression of various human cancers; however, the expression and role of CXC chemokines in pancreatic adenocarcinoma (PAAD) have not yet been identified. The aim of this study is to identify the expression patterns, clinical significance and mechanisms of CXC chemokines in regulating tumour microenvironment of PAAD. Three CXC chemokines, including CXCL5, CXCL9, and CXCL10, were significantly overexpressed in PAAD tissues, which were correlated with the poor survival of the patients. CXCL9/10 was associated with change of immune cell pattern in the tumour microenvironment, and supplementation of CXCL9 in the orthotopic murine PAAD model promoted tumour progression. In particular, CXCL9 reduced the CD8+ cytotoxic T lymphocytes in the tumour microenvironment of PAAD, which could be attributed to the reduced CD8+ T cell proliferation, activation, and secretion of anti-tumour cytokines. In vitro treatment of CXCL9 directly led to the suppression of the proliferation, activation, and secretion of anti-tumour cytokines of isolated CD8+ T cells. Inhibition of STAT3 recovered the CXCL9-inhibited proliferation, activation, and secretion of anti-tumour cytokines of CD8+ T cells. Our study indicates CXCL9 as a potential target of immunotherapy in PAAD treatment by regulating the CD8+ T lymphocytes in the tumour microenvironment.
Highlights
Pancreatic adenocarcinoma (PAAD), accounting for the most common form of pancreatic cancer, is one of the most malignant solid tumour among various types of tumours
Overexpression of CXCL5, CXCL9, and CXCL10 predicted with the poor prognosis of the patients (Figure 1C)
We found that CXCL9 was overexpressed in PAAD tissues compared with healthy adjacent pancreas
Summary
Pancreatic adenocarcinoma (PAAD), accounting for the most common form of pancreatic cancer, is one of the most malignant solid tumour among various types of tumours. 10–15% PAAD patients at very early stage could receive a curative resection, while a large number of patients may receive chemotherapy that gains minimal benefit to the outcome [2, 3], suggesting development of novel treatment targets and strategies is of great importance. Accumulating recent evidence has indicated that the tumour microenvironment of PAAD plays a critical role in the progression and metastasis of the tumour cells. The dynamic composition of the tumour microenvironment, including immune cells, cytokines, fibroblast, blood vessel and extracellular matrix, interact with tumour cells www.aging-us.com as well as with each other during the progression of preneoplastic pancreatic intraepithelial neoplasia to invasive PAAD [4]. Identification of targets on immune microenvironment may derive novel strategies in the treatment of PAAD
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