TY  - JOUR
AU  - Delvecchio
AU  - Fincham
AU  - Spear
AU  - Clear
AU  - Roy-Luzarraga
AU  - Balkwill
AU  - Gribben
AU  - Bombardieri
AU  - Hodivala-Dilke
AU  - Capasso, Melania
AU  - Kocher
TI  - Pancreatic Cancer Chemotherapy Is Potentiated by Induction of Tertiary Lymphoid Structures in Mice
JO  - Cellular and Molecular Gastroenterology and Hepatology
VL  - 12
IS  - 5
SN  - 2352-345X
CY  - New York, NY
PB  - Elsevier
M1  - DZNE-2021-01291
SP  - 1543-1565
PY  - 2021
N1  - CC BY
AB  - 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.
KW  - Animals
KW  - Antigen Presentation
KW  - Antineoplastic Agents: pharmacology
KW  - Antineoplastic Agents: therapeutic use
KW  - B-Lymphocytes: immunology
KW  - B-Lymphocytes: metabolism
KW  - B-Lymphocytes: pathology
KW  - Biomarkers
KW  - Carcinoma, Pancreatic Ductal: drug therapy
KW  - Carcinoma, Pancreatic Ductal: immunology
KW  - Carcinoma, Pancreatic Ductal: metabolism
KW  - Carcinoma, Pancreatic Ductal: pathology
KW  - Cell Line, Tumor
KW  - Cytokines: metabolism
KW  - Dendritic Cells: immunology
KW  - Dendritic Cells: metabolism
KW  - Disease Models, Animal
KW  - Germinal Center
KW  - Humans
KW  - Immunohistochemistry
KW  - Mice
KW  - Mice, Transgenic
KW  - Pancreatic Neoplasms: drug therapy
KW  - Pancreatic Neoplasms: immunology
KW  - Pancreatic Neoplasms: metabolism
KW  - Pancreatic Neoplasms: pathology
KW  - T-Lymphocytes: immunology
KW  - T-Lymphocytes: metabolism
KW  - T-Lymphocytes: pathology
KW  - Tertiary Lymphoid Structures: drug therapy
KW  - Tertiary Lymphoid Structures: immunology
KW  - Tertiary Lymphoid Structures: pathology
KW  - Treatment Outcome
KW  - Tumor Microenvironment: drug effects
KW  - Tumor Microenvironment: immunology
KW  - Xenograft Model Antitumor Assays
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC8529396
C6  - pmid:34252585
DO  - DOI:10.1016/j.jcmgh.2021.06.023
UR  - https://pub.dzne.de/record/157917
ER  -