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000157917 0247_ $$2doi$$a10.1016/j.jcmgh.2021.06.023
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000157917 037__ $$aDZNE-2021-01291
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000157917 1001_ $$0P:(DE-HGF)0$$aDelvecchio$$b0
000157917 245__ $$aPancreatic Cancer Chemotherapy Is Potentiated by Induction of Tertiary Lymphoid Structures in Mice
000157917 260__ $$aNew York, NY$$bElsevier$$c2021
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000157917 520__ $$aBackground and aims: The presence of tertiary lymphoid structures (TLSs) may confer survival benefit to patients with pancreatic ductal adenocarcinoma (PDAC), in an otherwise immunologically inert malignancy. Yet, the precise role in PDAC has not been elucidated. Here, we aim to investigate the structure and role of TLSs in human and murine pancreatic cancer.Methods: Multicolor immunofluorescence and immunohistochemistry were used to fully characterize TLSs in human and murine (transgenic [KPC (KrasG12D, p53R172H, Pdx-1-Cre)] and orthotopic) pancreatic cancer. An orthotopic murine model was developed to study the development of TLSs and the effect of the combined chemotherapy and immunotherapy on tumor growth.Results: Mature, functional TLSs are not ubiquitous in human PDAC and KPC murine cancers and are absent in the orthotopic murine model. TLS formation can be induced in the orthotopic model of PDAC after intratumoral injection of lymphoid chemokines (CXCL13/CCL21). Coadministration of systemic chemotherapy (gemcitabine) and intratumoral lymphoid chemokines into orthotopic tumors altered immune cell infiltration ,facilitating TLS induction and potentiating antitumor activity of chemotherapy. This resulted in significant tumor reduction, an effect not achieved by either treatment alone. Antitumor activity seen after TLS induction is associated with B cell-mediated dendritic cell activation.Conclusions: This study provides supportive evidence that TLS induction may potentiate the antitumor activity of chemotherapy in a murine model of PDAC. A detailed understanding of TLS kinetics and their induction, owing to multiple host and tumor factors, may help design personalized therapies harnessing the potential of immune-oncology.
000157917 536__ $$0G:(DE-HGF)POF4-351$$a351 - Brain Function (POF4-351)$$cPOF4-351$$fPOF IV$$x0
000157917 536__ $$0G:(GEPRIS)390873048$$aEXC 2151: ImmunoSensation2 - the immune sensory system (390873048)$$c390873048$$x1
000157917 650_2 $$2MeSH$$aAnimals
000157917 650_2 $$2MeSH$$aAntigen Presentation
000157917 650_2 $$2MeSH$$aAntineoplastic Agents: pharmacology
000157917 650_2 $$2MeSH$$aAntineoplastic Agents: therapeutic use
000157917 650_2 $$2MeSH$$aB-Lymphocytes: immunology
000157917 650_2 $$2MeSH$$aB-Lymphocytes: metabolism
000157917 650_2 $$2MeSH$$aB-Lymphocytes: pathology
000157917 650_2 $$2MeSH$$aBiomarkers
000157917 650_2 $$2MeSH$$aCarcinoma, Pancreatic Ductal: drug therapy
000157917 650_2 $$2MeSH$$aCarcinoma, Pancreatic Ductal: immunology
000157917 650_2 $$2MeSH$$aCarcinoma, Pancreatic Ductal: metabolism
000157917 650_2 $$2MeSH$$aCarcinoma, Pancreatic Ductal: pathology
000157917 650_2 $$2MeSH$$aCell Line, Tumor
000157917 650_2 $$2MeSH$$aCytokines: metabolism
000157917 650_2 $$2MeSH$$aDendritic Cells: immunology
000157917 650_2 $$2MeSH$$aDendritic Cells: metabolism
000157917 650_2 $$2MeSH$$aDisease Models, Animal
000157917 650_2 $$2MeSH$$aGerminal Center
000157917 650_2 $$2MeSH$$aHumans
000157917 650_2 $$2MeSH$$aImmunohistochemistry
000157917 650_2 $$2MeSH$$aMice
000157917 650_2 $$2MeSH$$aMice, Transgenic
000157917 650_2 $$2MeSH$$aPancreatic Neoplasms: drug therapy
000157917 650_2 $$2MeSH$$aPancreatic Neoplasms: immunology
000157917 650_2 $$2MeSH$$aPancreatic Neoplasms: metabolism
000157917 650_2 $$2MeSH$$aPancreatic Neoplasms: pathology
000157917 650_2 $$2MeSH$$aT-Lymphocytes: immunology
000157917 650_2 $$2MeSH$$aT-Lymphocytes: metabolism
000157917 650_2 $$2MeSH$$aT-Lymphocytes: pathology
000157917 650_2 $$2MeSH$$aTertiary Lymphoid Structures: drug therapy
000157917 650_2 $$2MeSH$$aTertiary Lymphoid Structures: immunology
000157917 650_2 $$2MeSH$$aTertiary Lymphoid Structures: pathology
000157917 650_2 $$2MeSH$$aTreatment Outcome
000157917 650_2 $$2MeSH$$aTumor Microenvironment: drug effects
000157917 650_2 $$2MeSH$$aTumor Microenvironment: immunology
000157917 650_2 $$2MeSH$$aXenograft Model Antitumor Assays
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000157917 773__ $$0PERI:(DE-600)2819778-1$$a10.1016/j.jcmgh.2021.06.023$$n5$$p1543-1565$$tCellular and Molecular Gastroenterology and Hepatology$$v12$$x2352-345X$$y2021
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