Characterization and oncolytic virus targeting of FAP-expressing tumor-associated pericytes in glioblastoma
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RESEARCH
Characterization and oncolytic virus targeting of FAP‑expressing tumor‑associated pericytes in glioblastoma Ming Li1, Guoping Li2, Juri Kiyokawa1, Zain Tirmizi1, Leland G. Richardson1, Jianfang Ning1,4, Saumya Das2, Robert L. Martuza1, Anat Stemmer‑Rachamimov3, Samuel D. Rabkin1* and Hiroaki Wakimoto1*
Abstract Cancer-associated fibroblasts (CAFs) are activated fibroblasts constituting the major stromal components in many types of cancer. CAFs contribute to hallmarks of cancer such as proliferation, invasion and immunosuppressive tumor microenvironment, and are associated with poor prognosis of patients with cancer. However, in glioblastoma (GBM), the most common and aggressive primary malignant brain tumor, our knowledge about CAFs or CAF-like stromal cells is limited. Here, using commonly accepted CAF markers, we characterized CAF-like cell populations in clinical glioma specimens and datasets along with mouse models of GBM. We found that tumor-associated pericytes marked by co-expression of fibroblast activation protein α (FAP) and PDGFRβ represent major stromal cell subsets in both human GBM and mouse GBM models, while a fraction of mesenchymal neoplastic cells also express FAP in patient tumors. Since oncolytic viruses can kill cancer cells and simultaneously modulate the tumor microenvironment by impacting non-neoplastic populations such as immune cells and tumor vasculature, we further investigated the abil‑ ity of oncolytic viruses to target GBM-associated stromal cells. An oncolytic adenovirus, ICOVIR15, carrying ∆24-E1A and an RGD-fiber, infects and depletes FAP+ pericytes as well as GBM cells in murine GBM. Our study thus identifies FAP+/PDGFRβ+ pericytes as a major CAF-like stromal cell population in GBM, and highlights the unique property of this oncolytic adenovirus to target both GBM cells and GBM-associated stromal FAP+ cells. Keywords: Glioblastoma, Tumor-associated fibroblasts, Pericytes, Oncolytic virus, FAP Introduction Cancer-associated fibroblasts (CAFs) are activated fibroblasts constituting the major stromal component in many types of cancer, including breast, lung, and pancreatic cancers [1–3]. A growing body of evidence indicates that CAFs play a crucial role in tumor development and progression [4]. CAFs drive the synthesis and remodeling of extracellular matrix, closely interact with cancer cells to promote their proliferation and migration, and *Correspondence: [email protected]; [email protected] 1 Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, USA Full list of author information is available at the end of the article
participate in angiogenesis and inflammation via the secretion of cytokines. Recent research further reveals that CAFs contribute to cancer progression via evasion of immune surveillance, and providing resistance to immunotherapy [5–7]. CAFs are heterogenous populations that display distinct protein profiles and have multiple cells of origin, including resi
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