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

Abstract

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.

Pancreatic ductal adenocarcinoma: biological hallmarks, current status, and future perspectives of combined modality treatment approaches

“…Apart from its potential to induce tumor cell death, radiotherapy is known to recondition the tumor microenvironment and to stimulate systemic anti-tumor immune responses – a phenomenon summarized as abscopal effects of radiotherapy [266–268]. However, in the monotherapy setting, radiation is often not sufficient to break the immunosuppressive milieu of established tumors, and combinations with immunostimulating agents are required.…”

Homoharringtonine suppresses tumor proliferation and migration by regulating EphB4-mediated β-catenin loss in hepatocellular carcinoma

“…Studies on the expression of EphB4 in numerous cancer types have shown overexpressed level in breast, colorectal, lung, and blood cancers correlating with poor prognosis 11 – 13 . It has been reported that high EphB4 expression enhanced the growth and migration of pancreatic, colorectal and papillary thyroid carcinoma, and such effect could be reversed by EphB4 knockdown, making EphB4 a promising target for cancer treatment 14 – 16 . Our previous study has confirmed the high expression of EphB4 in HCC 17 , and its function in HCC migration remains poorly understood.…”

Tyrosine Phosphoproteomics of Patient-Derived Xenografts Reveals Ephrin Type-B Receptor 4 Tyrosine Kinase as a Therapeutic Target in Pancreatic Cancer

“…The discrepancy observed could be due to different detection techniques used. The total EphB4 expression was also seen to be higher in pancreatic cancer; however, relatively lower expression in the normal pancreas [ 29 ]. Public data repositories such as GTEx ( (accessed on 2 June 2021)) and the Human Protein Atlas ( (accessed on 2 June 2021)) show lower expression of EphB4 in the pancreas but a relatively higher expression in pancreatic cancer.…”

“…The discrepancy observed could be due to different detection techniques used. The total EphB4 expression was also seen to be higher in pancreatic cancer; however, relatively lower expression in the normal pancreas [29]. Public data repositories such as GTEx (https://www.…”

“…gtexportal.org/home/gene/EPHB4 (accessed on 2 June 2021)) and the Human Protein Atlas (https://www.proteinatlas.org/ENSG00000196411-EPHB4/tissue/primary+data (accessed on 2 June 2021)) show lower expression of EphB4 in the pancreas but a relatively higher expression in pancreatic cancer. The study by Lennon et al indicated a role of EphB4-EphrinB2 in the treatment of resistance to radiotherapy in pancreatic ductal adenocarcinoma [29]. The study showed the involvement of the tumor microenvironment in the release of immunosuppressive factors, thereby contributing to tumor progression, and targeted therapies in combination with radiotherapy could arrest the tumor growth.…”