Pancreatic Tumor Microenvironment Modulation by EphB4-ephrinB2 Inhibition and Radiation Combination

Clin Cancer Res. 2019 Jun 1;25(11):3352-3365. doi: 10.1158/1078-0432.CCR-18-2811. Epub 2019 Apr 3.


Purpose: A driving factor in pancreatic ductal adenocarcinoma (PDAC) treatment resistance is the tumor microenvironment, which is highly immunosuppressive. One potent immunologic adjuvant is radiotherapy. Radiation, however, has also been shown to induce immunosuppressive factors, which can contribute to tumor progression and formation of fibrotic tumor stroma. To capitalize on the immunogenic effects of radiation and obtain a durable tumor response, radiation must be rationally combined with targeted therapies to mitigate the influx of immunosuppressive cells and fibrosis. One such target is ephrinB2, which is overexpressed in PDAC and correlates negatively with prognosis.Experimental Design: On the basis of previous studies of ephrinB2 ligand-EphB4 receptor signaling, we hypothesized that inhibition of ephrinB2-EphB4 combined with radiation can regulate the microenvironment response postradiation, leading to increased tumor control in PDAC. This hypothesis was explored using both cell lines and in vivo human and mouse tumor models.

Results: Our data show this treatment regimen significantly reduces regulatory T-cell, macrophage, and neutrophil infiltration and stromal fibrosis, enhances effector T-cell activation, and decreases tumor growth. Furthermore, our data show that depletion of regulatory T cells in combination with radiation reduces tumor growth and fibrosis.

Conclusions: These are the first findings to suggest that in PDAC, ephrinB2-EphB4 interaction has a profibrotic, protumorigenic role, presenting a novel and promising therapeutic target.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / pharmacology
  • Antineoplastic Agents, Immunological / therapeutic use
  • Biomarkers
  • Cell Line, Tumor
  • Disease Models, Animal
  • Ephrin-B2 / antagonists & inhibitors
  • Ephrin-B2 / genetics
  • Ephrin-B2 / metabolism*
  • Female
  • Flow Cytometry
  • Gene Expression
  • Gene Knockdown Techniques
  • Humans
  • Immunohistochemistry
  • Mice
  • Molecular Targeted Therapy / adverse effects
  • Molecular Targeted Therapy / methods
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology*
  • Pancreatic Neoplasms / therapy
  • Radiotherapy / adverse effects
  • Radiotherapy / methods
  • Receptor, EphB4 / antagonists & inhibitors
  • Receptor, EphB4 / genetics
  • Receptor, EphB4 / metabolism*
  • Signal Transduction / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Tumor Microenvironment / drug effects*
  • Tumor Microenvironment / radiation effects*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents, Immunological
  • Biomarkers
  • Ephrin-B2
  • Receptor, EphB4