Dual Stromal Targeting Sensitizes Pancreatic Adenocarcinoma for Anti-Programmed Cell Death Protein 1 Therapy.

Humans Mice Animals Pancreatic Neoplasms / pathology Adenocarcinoma / pathology Hyaluronoglucosaminidase / pharmacology Hyaluronic Acid Carcinoma, Pancreatic Ductal / genetics Liver Neoplasms / drug therapy Focal Adhesion Protein-Tyrosine Kinases Cytokines / pharmacology Cell Death Polyethylene Glycols / therapeutic use Tumor Microenvironment Pancreatic Neoplasms
Anti–PD-1 Antibody CXCR4 FAK Hyaluronan Pancreatic Ductal Adenocarcinoma

Journal

Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630

Informations de publication

Date de publication:
11 2022
Historique:
received: 11 04 2022
revised: 27 05 2022
accepted: 07 06 2022
pubmed: 20 6 2022
medline: 26 10 2022
entrez: 19 6 2022
Statut: ppublish

Résumé

The stroma in pancreatic ductal adenocarcinoma (PDAC) contributes to its immunosuppressive nature and therapeutic resistance. Herein we sought to modify signaling and enhance immunotherapy efficacy by targeting multiple stromal components through both intracellular and extracellular mechanisms. A murine liver metastasis syngeneic model of PDAC was treated with focal adhesion kinase inhibitor (FAKi), anti-programmed cell death protein 1 (PD-1) antibody, and stromal hyaluronan (HA) degradation by PEGylated recombinant human hyaluronidase (PEGPH20) to assess immune and stromal modulating effects of these agents and their combinations. The results showed that HA degradation by PEGPH20 and reduction in phosphorylated FAK expression by FAKi leads to improved survival in PDAC-bearing mice treated with anti-PD-1 antibody. HA degradation in combination with FAKi and anti-PD-1 antibody increases T-cell infiltration and alters T-cell phenotype toward effector memory T cells. FAKi alters the expression of T-cell modulating cytokines and leads to changes in T-cell metabolism and increases in effector T-cell signatures. HA degradation in combination with anti-PD-1 antibody and FAKi treatments reduces granulocytes, including granulocytic- myeloid-derived suppressor cells and decreases C-X-C chemokine receptor type 4 (CXCR4)-expressing myeloid cells, particularly the CXCR4-expressing granulocytes. Anti-CXCR4 antibody combined with FAKi and anti-PD-1 antibody significantly decreases metastatic rates in the PDAC liver metastasis model. This represents the first preclinical study to identify synergistic effects of targeting both intracellular and extracellular components within the PDAC stroma and supports testing anti-CXCR4 antibody in combination with FAKi as a PDAC treatment strategy.

Sections du résumé

BACKGROUND & AIMS
The stroma in pancreatic ductal adenocarcinoma (PDAC) contributes to its immunosuppressive nature and therapeutic resistance. Herein we sought to modify signaling and enhance immunotherapy efficacy by targeting multiple stromal components through both intracellular and extracellular mechanisms.
METHODS
A murine liver metastasis syngeneic model of PDAC was treated with focal adhesion kinase inhibitor (FAKi), anti-programmed cell death protein 1 (PD-1) antibody, and stromal hyaluronan (HA) degradation by PEGylated recombinant human hyaluronidase (PEGPH20) to assess immune and stromal modulating effects of these agents and their combinations.
RESULTS
The results showed that HA degradation by PEGPH20 and reduction in phosphorylated FAK expression by FAKi leads to improved survival in PDAC-bearing mice treated with anti-PD-1 antibody. HA degradation in combination with FAKi and anti-PD-1 antibody increases T-cell infiltration and alters T-cell phenotype toward effector memory T cells. FAKi alters the expression of T-cell modulating cytokines and leads to changes in T-cell metabolism and increases in effector T-cell signatures. HA degradation in combination with anti-PD-1 antibody and FAKi treatments reduces granulocytes, including granulocytic- myeloid-derived suppressor cells and decreases C-X-C chemokine receptor type 4 (CXCR4)-expressing myeloid cells, particularly the CXCR4-expressing granulocytes. Anti-CXCR4 antibody combined with FAKi and anti-PD-1 antibody significantly decreases metastatic rates in the PDAC liver metastasis model.
CONCLUSIONS
This represents the first preclinical study to identify synergistic effects of targeting both intracellular and extracellular components within the PDAC stroma and supports testing anti-CXCR4 antibody in combination with FAKi as a PDAC treatment strategy.

Identifiants

DOI: 10.1053/j.gastro.2022.06.027 PMID: 35718227 PMC: PMC9613523
pubmed: 35718227
pii: S0016-5085(22)00645-X
doi: 10.1053/j.gastro.2022.06.027
pmc: PMC9613523
mid: NIHMS1817335
pii:
doi:

Substances chimiques

Hyaluronoglucosaminidase EC 3.2.1.35
Hyaluronic Acid 9004-61-9
Focal Adhesion Protein-Tyrosine Kinases EC 2.7.10.2
Cytokines 0
Polyethylene Glycols 3WJQ0SDW1A

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

1267-1280.e7

Subventions

Organisme : NCI NIH HHS
ID : K08 CA259456
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA247886
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA126607
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA197296
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA169702
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA062924
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA006973
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.

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Auteurs

Alex B Blair (AB)

Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Multidisciplinary Gastrointestinal Cancer Laboratories Program, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Jianxin Wang (J)

Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, Maryland.

John Davelaar (J)

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

Andrew Baker (A)

Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Keyu Li (K)

Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Nan Niu (N)

Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Junke Wang (J)

Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Yingkuan Shao (Y)

Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Vanessa Funes (V)

Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Multidisciplinary Gastrointestinal Cancer Laboratories Program, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Pan Li (P)

Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Jonathan A Pachter (JA)

Verastem Oncology, Needham, Massachusetts.

Daniel C Maneval (DC)

Halozyme Therapeutics, Inc, San Diego, California.

Felipe Dezem (F)

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

Jasmine Plummer (J)

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

Keith Syson Chan (KS)

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

Jun Gong (J)

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

Andrew E Hendifar (AE)

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

Stephen J Pandol (SJ)

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

Richard Burkhart (R)

Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Multidisciplinary Gastrointestinal Cancer Laboratories Program, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Yuqing Zhang (Y)

Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.

Lei Zheng (L)

Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Multidisciplinary Gastrointestinal Cancer Laboratories Program, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: lzheng6@jhmi.edu.

Arsen Osipov (A)

Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Multidisciplinary Gastrointestinal Cancer Laboratories Program, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address: arsen.osipov@cshs.org.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Dual Stromal Targeting Sensitizes Pancreatic...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Dual Stromal Targeting Sensitizes Pancreatic...
questionsmedicales.fr › Eucaryotes › Animaux › Dual Stromal Targeting Sensitizes Pancreatic...
questionsmedicales.fr › Maladies endocriniennes › Tumeurs des glandes endocrines › Tumeurs du pancréas › Dual Stromal Targeting Sensitizes Pancreatic...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Carcinomes › Adénocarcinome › Dual Stromal Targeting Sensitizes Pancreatic...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Lyases › Carbon-oxygen lyases › Polysaccharide-lyases › Hyaluronoglucosaminidase › Dual Stromal Targeting Sensitizes Pancreatic...
questionsmedicales.fr › Glucides › Polyosides › Glycosaminoglycanes › Acide hyaluronique › Dual Stromal Targeting Sensitizes Pancreatic...
questionsmedicales.fr › Maladies endocriniennes › Tumeurs des glandes endocrines › Tumeurs du pancréas › Carcinome du canal pancréatique › Dual Stromal Targeting Sensitizes Pancreatic...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Tumeurs du foie › Dual Stromal Targeting Sensitizes Pancreatic...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-tyrosine kinases › Focal adhesion protein-tyrosine kinases › Dual Stromal Targeting Sensitizes Pancreatic...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Dual Stromal Targeting Sensitizes Pancreatic...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Dual Stromal Targeting Sensitizes Pancreatic...
questionsmedicales.fr › Technologie, industrie et agriculture › Produits manufacturés › Matériaux biomédicaux et dentaires › Polymères › Polyéthylène glycols › Dual Stromal Targeting Sensitizes Pancreatic...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Microenvironnement cellulaire › Microenvironnement tumoral › Dual Stromal Targeting Sensitizes Pancreatic...
questionsmedicales.fr › Maladies endocriniennes › Tumeurs des glandes endocrines › Tumeurs du pancréas › Dual Stromal Targeting Sensitizes Pancreatic...