CXCL10/CXCR3 signaling contributes to an inflammatory microenvironment and its blockade enhances progression of murine pancreatic precancerous lesions

• Published in: eLife 2021-07, Vol.10
• Main Authors: Pandey, Veethika, Fleming-Martinez, Alicia, Bastea, Ligia, Doeppler, Heike R, Eisenhauer, Jillian, Le, Tam, Edenfield, Brandy, Storz, Peter
• Format: Article
• Language: English
• Subjects: Animals; Biotechnology industry; Cancer Biology; Cell activation; Cell Biology; Cells, Cultured; Chemokine CXCL10 - antagonists & inhibitors; Chemokine CXCL10 - genetics; Chemokine CXCL10 - immunology; Chemokine CXCL10 - metabolism; Chemokines; CXCL10; CXCL10 protein; CXCR3; CXCR3 protein; Cytokines; Development and progression; Disease Models, Animal; Disease Progression; Experiments; Female; Fibrosis; Infections; Inflammation; Inflammation - etiology; Inflammation - immunology; Lesions; Macrophages; Macrophages - immunology; Male; Mice; Microenvironments; Pancreas - cytology; Pancreas - immunology; Pancreas - pathology; Pancreatic cancer; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - physiopathology; Phenotypes; Proteins; Receptors, CXCR3 - antagonists & inhibitors; Receptors, CXCR3 - genetics; Receptors, CXCR3 - immunology; Receptors, CXCR3 - metabolism; Scientific equipment and supplies industry; Signal Transduction; Standard deviation; Statistical analysis; Tumor Microenvironment - immunology; Tumors; γ-Interferon
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.60646

The development of pancreatic cancer requires recruitment and activation of different macrophage populations. However, little is known about how macrophages are attracted to the pancreas after injury or an oncogenic event, and how they crosstalk with lesion cells or other cells of the lesion microenvironment. Here, we delineate the importance of CXCL10/CXCR3 signaling during the early phase of murine pancreatic cancer. We show that CXCL10 is produced by pancreatic precancerous lesion cells in response to IFNγ signaling and that inflammatory macrophages are recipients for this chemokine. CXCL10/CXCR3 signaling in macrophages mediates their chemoattraction to the pancreas, enhances their proliferation, and maintains their inflammatory identity. Blocking of CXCL10/CXCR3 signaling in vivo shifts macrophage populations to a tumor-promoting (Ym1 , Fizz , Arg1 ) phenotype, increases fibrosis, and mediates progression of lesions, highlighting the importance of this pathway in PDA development. This is reversed when CXCL10 is overexpressed in PanIN cells.