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 3

Tem1-TT vaccination controls tumor progression.

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Tem1-TT vaccination controls tumor progression. (A) Tumor control in a p...
(A) Tumor control in a prophylactic setting. BALB/c and C57BL/6 mice were immunized 3 times with Tem1, TT, or Tem1-TT vaccines, then injected s.c. with 1 × 105 CT26, TC1, or LLC cells. Data are mean ± SD (n = 10 per group) from 1 of 5 experiments. P < 0.05, Tem1-TT vs. Tem1 and Tem1-TT vs. TT (CT26, TC1, and LLC), pairwise multiple-comparison Tukey test. (B and C) Inhibition of CT26 and TC1 tumor progression and induction of CD3+ T cell infiltration in a therapeutic setting. BALB/c mice were injected s.c. with 1 × 105 CT26 cells (B), and C57BL/6 mice were injected with 1 × 105 TC1 cells (C). Mice were immunized 1 day, 1 week, and 2 weeks later with Tem1, TT, or Tem1-TT vaccine and euthanized 33 (B) or 29 (C) days after tumor challenge. Left: Data points are mean ± SD (n = 10 mice/group) from 1 of 3 experiments. P < 0.05, Tem1-TT vs. Tem1 and Tem1-TT vs. TT (CT26 and TC1), Tukey test. CD3+ T cells in corresponding tumor sections and quantification are also shown. Original magnification, ×20. Data are mean ± SD of a representative experiment (n = 5 per group).