Pancreatic Cancer Chemotherapy Is Potentiated by Induction of Tertiary Lymphoid Structures in MiceSummary

Background 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 stru...

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Autores principales:	Francesca R. Delvecchio, Rachel E.A. Fincham, Sarah Spear, Andrew Clear, Marina Roy-Luzarraga, Frances R. Balkwill, John G. Gribben, Michele Bombardieri, Kairbaan Hodivala-Dilke, Melania Capasso, Hemant M. Kocher
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	B Cells T Cells Dendritic Cells Orthotopic Transgenic Mice Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/b635dee8c698441ab3175efcb13b1c08
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spelling	oai:doaj.org-article:b635dee8c698441ab3175efcb13b1c082021-11-12T04:38:35ZPancreatic Cancer Chemotherapy Is Potentiated by Induction of Tertiary Lymphoid Structures in MiceSummary2352-345X10.1016/j.jcmgh.2021.06.023https://doaj.org/article/b635dee8c698441ab3175efcb13b1c082021-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X21001387https://doaj.org/toc/2352-345XBackground 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.Francesca R. DelvecchioRachel E.A. FinchamSarah SpearAndrew ClearMarina Roy-LuzarragaFrances R. BalkwillJohn G. GribbenMichele BombardieriKairbaan Hodivala-DilkeMelania CapassoHemant M. KocherElsevierarticleB CellsT CellsDendritic CellsOrthotopicTransgenic MiceDiseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 5, Pp 1543-1565 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	B Cells T Cells Dendritic Cells Orthotopic Transgenic Mice Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	B Cells T Cells Dendritic Cells Orthotopic Transgenic Mice Diseases of the digestive system. Gastroenterology RC799-869 Francesca R. Delvecchio Rachel E.A. Fincham Sarah Spear Andrew Clear Marina Roy-Luzarraga Frances R. Balkwill John G. Gribben Michele Bombardieri Kairbaan Hodivala-Dilke Melania Capasso Hemant M. Kocher Pancreatic Cancer Chemotherapy Is Potentiated by Induction of Tertiary Lymphoid Structures in MiceSummary
description	Background 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.
format	article
author	Francesca R. Delvecchio Rachel E.A. Fincham Sarah Spear Andrew Clear Marina Roy-Luzarraga Frances R. Balkwill John G. Gribben Michele Bombardieri Kairbaan Hodivala-Dilke Melania Capasso Hemant M. Kocher
author_facet	Francesca R. Delvecchio Rachel E.A. Fincham Sarah Spear Andrew Clear Marina Roy-Luzarraga Frances R. Balkwill John G. Gribben Michele Bombardieri Kairbaan Hodivala-Dilke Melania Capasso Hemant M. Kocher
author_sort	Francesca R. Delvecchio
title	Pancreatic Cancer Chemotherapy Is Potentiated by Induction of Tertiary Lymphoid Structures in MiceSummary
title_short	Pancreatic Cancer Chemotherapy Is Potentiated by Induction of Tertiary Lymphoid Structures in MiceSummary
title_full	Pancreatic Cancer Chemotherapy Is Potentiated by Induction of Tertiary Lymphoid Structures in MiceSummary
title_fullStr	Pancreatic Cancer Chemotherapy Is Potentiated by Induction of Tertiary Lymphoid Structures in MiceSummary
title_full_unstemmed	Pancreatic Cancer Chemotherapy Is Potentiated by Induction of Tertiary Lymphoid Structures in MiceSummary
title_sort	pancreatic cancer chemotherapy is potentiated by induction of tertiary lymphoid structures in micesummary
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/b635dee8c698441ab3175efcb13b1c08
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Pancreatic Cancer Chemotherapy Is Potentiated by Induction of Tertiary Lymphoid Structures in MiceSummary

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