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 8

Proposed mechanism of action of Tem1-TT vaccination.

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Proposed mechanism of action of Tem1-TT vaccination. (i) Tem1-TT vaccine...
(i) Tem1-TT vaccine induces expansion of TEM1-specific CD8+ T cells that target the CT26 tumor vasculature. These cytolytic effectors target and kill TEM1-expressing cells, most likely tumor-associated endothelial cells and/or pericytes. (ii) This event results in reduction of the tumor vasculature, inducing inflammation and tumor hypoxia, which results in localized tumor cell death. (iii) Dead tumor cells are scavenged by APCs, which process relevant tumor-associated antigens (TAA; e.g., AH1 antigen in CT26 tumor model). (iv) This cross-presentation event results in a secondary cross-priming event that expands tumor-specific cytotoxic CD8+ T cells to tumor cell–derived epitopes. (v) Tumor-specific cytotoxic CD8+ T cells lyse and eliminate tumor cells, resulting in control of tumor growth.