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Updated: Sep 7, 2025
Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma
Published on: November 19, 2019
Dual Stromal Targeting Sensitizes Pancreatic Adenocarcinoma for Anti-Programmed Cell Death Protein 1 Therapy
Alex B Blair1, Jianxin Wang2, John Davelaar3
1Department 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.
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.
Insights
Targeting pancreatic cancer stroma with hyaluronan degradation and focal adhesion kinase inhibition enhances anti-PD-1 immunotherapy. This combination therapy boosts T-cell infiltration and reduces immunosuppressive cells, improving survival and decreasing metastasis.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) stroma promotes immune suppression and treatment resistance.
- Targeting stromal components offers a strategy to enhance immunotherapy efficacy.
Purpose of the Study:
- To investigate the effects of targeting intracellular and extracellular stromal components in PDAC.
- To assess the combination of focal adhesion kinase inhibitor (FAKi), anti-programmed cell death protein 1 (PD-1) antibody, and hyaluronan (HA) degradation via PEGylated recombinant human hyaluronidase (PEGPH20).
Main Methods:
- A syngeneic murine liver metastasis model of PDAC was utilized.
- Mice were treated with FAKi, anti-PD-1 antibody, and PEGPH20, alone and in combination.
- Immune and stromal responses, survival, and metastasis were evaluated.
Main Results:
- Combination therapy, including HA degradation and FAKi with anti-PD-1, improved survival.
- This approach increased T-cell infiltration and promoted an effector memory T-cell phenotype.
- Treatments reduced immunosuppressive granulocytes and CXCR4-expressing myeloid cells, with anti-CXCR4 antibody further decreasing metastasis.
Conclusions:
- This study demonstrates synergistic effects of targeting both intracellular and extracellular PDAC stroma.
- Combining anti-CXCR4 antibody with FAKi and anti-PD-1 antibody is a promising strategy for PDAC treatment.
