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Tumor endothelial marker 1-specific DNA vaccination targets tumor vasculature.

ABSTRACT: Tumor endothelial marker 1 (TEM1; also known as endosialin or CD248) is a protein found on tumor vasculature and in tumor stroma. Here, we tested whether TEM1 has potential as a therapeutic target for cancer immunotherapy by immunizing immunocompetent mice with Tem1 cDNA fused to the minimal domain of the C fragment of tetanus toxoid (referred to herein as Tem1-TT vaccine). Tem1-TT vaccination elicited CD8+ and/or CD4+ T cell responses against immunodominant TEM1 protein sequences. Prophylactic immunization of animals with Tem1-TT prevented or delayed tumor formation in several murine tumor models. Therapeutic vaccination of tumor-bearing mice reduced tumor vascularity, increased infiltration of CD3+ T cells into the tumor, and controlled progression of established tumors. Tem1-TT vaccination also elicited CD8+ cytotoxic T cell responses against murine tumor-specific antigens. Effective Tem1-TT vaccination did not affect angiogenesis-dependent physiological processes, including wound healing and reproduction. Based on these data and the widespread expression of TEM1 on the vasculature of different tumor types, we conclude that targeting TEM1 has therapeutic potential in cancer immunotherapy.

SUBMITTER: Facciponte JG

PROVIDER: S-EPMC3973096 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Tumor endothelial marker 1-specific DNA vaccination targets tumor vasculature.

Facciponte John G JG Ugel Stefano S De Sanctis Francesco F Li Chunsheng C Wang Liping L Nair Gautham G Sehgal Sandy S Raj Arjun A Matthaiou Efthymia E Coukos George G Facciabene Andrea A

The Journal of clinical investigation 20140318 4

Tumor endothelial marker 1 (TEM1; also known as endosialin or CD248) is a protein found on tumor vasculature and in tumor stroma. Here, we tested whether TEM1 has potential as a therapeutic target for cancer immunotherapy by immunizing immunocompetent mice with Tem1 cDNA fused to the minimal domain of the C fragment of tetanus toxoid (referred to herein as Tem1-TT vaccine). Tem1-TT vaccination elicited CD8+ and/or CD4+ T cell responses against immunodominant TEM1 protein sequences. Prophylactic ...[more]

PMID: 24642465

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Project description:Tumor angiogenesis is characterized by abnormal vessel morphology leading to erratic and insufficient delivery of chemotherapeutics and oxygen, making the tumor core not only highly hypoxic but also unresponsive toward treatment. Such hypoxic conditions promote tumor aggressiveness, leading to the establishment of metastatic disease. Most anti-angiogenic treatments aim toward the destruction of tumor vasculature, which proves countereffective by further increasing its aggressive nature. Hence, developing drugs which target or regulate these processes might lead to a better delivery of chemotherapeutics resulting in tumor shrinkage. Plant-derived natural compounds having a bioactive ingredient, especially triterpenoids, have been known to possess anticancer properties. AECHL-1, a recently isolated novel triterpenoid with proven anticancer potential, is seemingly noncytotoxic toward HEK 293 and HUVECs. Also, cytotoxicity was absent during in vivo studies involving intraperitoneal injections with 5 µg/kg body weight AECHL-1 on SCID mice. When used at subtoxic doses, it was found to be effective in suppression of neo-vessel formation as demonstrated in the chick chorioallantoic membrane, rat aortic rings, Matrigel plugs and xenograft tumors implanted in SCID mice. Tumor vasculature from AECHL-1-treated mice showed greater mural cell coverage and relatively normalized architecture. Investigations into the molecular mechanisms responsible for these observations revealed an effect on the actin cytoskeleton of stimulated HUVECs as well as the VEGFR2-mediated MAPK pathway. AECHL-1 could effectively distinguish between stimulated and nonstimulated endothelial cells. AECHL-1 could also downregulate HIF-1α expression and VEGF secretion under hypoxic conditions, thus reducing the fears of unnecessarily aggravating tumor metastasis as a result of anti-angiogenic therapy. Results obtained from the aforementioned studies make it clear that though AECHL-1 shows promise in discouraging and pruning neo-vasculature, it may not affect existing vasculature as the doses used for the assays are significantly lower than the ones causing endothelial cell death and has potential to be considered as a candidate for therapeutic drug development.

Dataset Information

Tumor endothelial marker 1-specific DNA vaccination targets tumor vasculature.

Publications

Tumor endothelial marker 1-specific DNA vaccination targets tumor vasculature.

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