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@ARTICLE{Delvecchio:157917,
author = {Delvecchio and Fincham and Spear and Clear and
Roy-Luzarraga and Balkwill and Gribben and Bombardieri and
Hodivala-Dilke and Capasso, Melania and Kocher},
title = {{P}ancreatic {C}ancer {C}hemotherapy {I}s {P}otentiated by
{I}nduction of {T}ertiary {L}ymphoid {S}tructures in {M}ice},
journal = {Cellular and Molecular Gastroenterology and Hepatology},
volume = {12},
number = {5},
issn = {2352-345X},
address = {New York, NY},
publisher = {Elsevier},
reportid = {DZNE-2021-01291},
pages = {1543-1565},
year = {2021},
note = {CC BY},
abstract = {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.},
keywords = {Animals / Antigen Presentation / Antineoplastic Agents:
pharmacology / Antineoplastic Agents: therapeutic use /
B-Lymphocytes: immunology / B-Lymphocytes: metabolism /
B-Lymphocytes: pathology / Biomarkers / Carcinoma,
Pancreatic Ductal: drug therapy / Carcinoma, Pancreatic
Ductal: immunology / Carcinoma, Pancreatic Ductal:
metabolism / Carcinoma, Pancreatic Ductal: pathology / Cell
Line, Tumor / Cytokines: metabolism / Dendritic Cells:
immunology / Dendritic Cells: metabolism / Disease Models,
Animal / Germinal Center / Humans / Immunohistochemistry /
Mice / Mice, Transgenic / Pancreatic Neoplasms: drug therapy
/ Pancreatic Neoplasms: immunology / Pancreatic Neoplasms:
metabolism / Pancreatic Neoplasms: pathology /
T-Lymphocytes: immunology / T-Lymphocytes: metabolism /
T-Lymphocytes: pathology / Tertiary Lymphoid Structures:
drug therapy / Tertiary Lymphoid Structures: immunology /
Tertiary Lymphoid Structures: pathology / Treatment Outcome
/ Tumor Microenvironment: drug effects / Tumor
Microenvironment: immunology / Xenograft Model Antitumor
Assays},
cin = {AG Capasso},
ddc = {610},
cid = {I:(DE-2719)1013033},
pnm = {351 - Brain Function (POF4-351) / EXC
2151: ImmunoSensation2 - the immune sensory system
(390873048)},
pid = {G:(DE-HGF)POF4-351 / G:(GEPRIS)390873048},
experiment = {EXP:(DE-2719)LMF-20190308},
typ = {PUB:(DE-HGF)16},
pmc = {pmc:PMC8529396},
pubmed = {pmid:34252585},
doi = {10.1016/j.jcmgh.2021.06.023},
url = {https://pub.dzne.de/record/157917},
}