Research Paper Volume 12, Issue 1 pp 502—517
CXCL9 chemokine promotes the progression of human pancreatic adenocarcinoma through STAT3-dependent cytotoxic T lymphocyte suppression
- 1 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- 2 Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Received: June 27, 2019 Accepted: December 23, 2019 Published: January 8, 2020
https://doi.org/10.18632/aging.102638How to Cite
Copyright: © 2020 Gao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.
Abbreviations
CFSE: Carboxyfluorescein succinimidyl ester; CXCL: Chemokine (C-X-C motif) ligand; CXCR: C-X-C chemokine receptor; CTLs: Cytotoxic T lymphocytes; ELISA: Enzyme-linked immunosorbent assay; FOXP1: Forkhead Box P1; GEO: Gene expression omnibus; IFNγ: Interferon gamma; IL2: Interleukin-2; Jak2: Janus kinase 2; LIF: Leukemia inhibitory factor; MDSC: Myeloid-derived suppressive cells; PAAD: Pancreatic adenocarcinoma; PD-L1: Programmed death-ligand; STAT1: Signal transducer and activator of transcription 1; STAT3: Signal transducer and activator of transcription 3; TIMER: Tumor Immune Estimation Resource; TNFα: Tumor necrosis factor alpha; TAMs: Tumour-associated macrophages.