Tumor endothelial marker 1–specific DNA vaccination targets tumor vasculature
John G. Facciponte, … , George Coukos, Andrea Facciabene
John G. Facciponte, … , George Coukos, Andrea Facciabene
Published March 18, 2014
Citation Information: J Clin Invest. 2014;124(4):1497-1511. https://doi.org/10.1172/JCI67382.
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Research Article Oncology

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.

Authors

John G. Facciponte, Stefano Ugel, Francesco De Sanctis, Chunsheng Li, Liping Wang, Gautham Nair, Sandy Sehgal, Arjun Raj, Efthymia Matthaiou, George Coukos, Andrea Facciabene

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Figure 4

Tem1-TT vaccination inhibits CT26 tumor vascularization.

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Tem1-TT vaccination inhibits CT26 tumor vascularization. (A) Tem1-TT vac...
(A) Tem1-TT vaccination reduced tumor hemoglobin content. Tumors at approximately 200 mm3 were excised from TT- or Tem1-TT–vaccinated mice and inspected grossly. Tumors from Tem1-TT–vaccinated mice appeared pale relative to control tumors. Reduced hemoglobin levels in tumors from Tem1-TT–vaccinated mice were observed by ELISA. (B) Tem1-TT vaccine reduces tumor vascularity. Tumors from TT- or Tem1-TT–vaccinated mice were analyzed by Doppler ultrasound. Perfused tumor area and real blood flux are shown, measured and calculated by Doppler image analysis. (C) CT26 tumors from Tem1-TT–immunized mice had significantly decreased CD31 expression compared with TT vaccination. Also note the abnormal blood vessel shape. Original magnification, ×20. (D) CAIX expression was increased in tumors from Tem1-TT–immunized animals. CAIX expression was visualized by immunohistochemistry, and Caix was independently quantified by qRT-PCR in tumors from mice vaccinated with either TT or Tem1-TT. Original magnification, ×20. Data in A–D are mean ± SD of a representative experiment (n = 5 per group). Statistical analyses were performed with Student’s t test.