癌症研究
间质细胞
肿瘤微环境
纤维化
基质
肿瘤进展
体内
放射治疗
胰腺肿瘤
胰腺癌
医学
生物
免疫学
病理
癌症
内科学
肿瘤细胞
免疫组织化学
生物技术
作者
Shelby Lennon,Ayman Oweida,Dallin Milner,Andy V. Phan,Shilpa Bhatia,Benjamin Van Court,Laurel B. Darragh,Adam C. Mueller,David Raben,Jorge L. Martínez‐Torrecuadrada,Todd M. Pitts,Hilary Somerset,Kimberly R. Jordan,Kirk C. Hansen,Jason S. Williams,Wells A. Messersmith,Richard D. Schulick,Philip Owens,Karyn A. Goodman,Sana D. Karam
标识
DOI:10.1158/1078-0432.ccr-18-2811
摘要
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.
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