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 5

Tem1-TT vaccination induces secondary tumor cell–specific cytotoxic T cell responses in tumor-bearing mice.

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Tem1-TT vaccination induces secondary tumor cell–specific cytotoxic T ce...
BALB/c (A) and C57BL/6 (B) mice were challenged, vaccinated, and euthanized as in Figure 3, B and C, respectively. 1 × 106 splenocytes from TT-, Tem1-, or Tem1-TT–vaccinated mice were tested for their capacity to respond to the specific TEM1 peptide (TEM1516–530), and to AH1 antigen (A) or the TC1 tumor-associated E7 antigen (B). (A) Tem1-TT–vaccinated splenocytes mounted specific responses against the immunodominant peptide of TEM1 (TEM1516–530) and the AH1 antigen, but not control peptide (TEM1506–520), as measured by ELISpot. Tem1-TT induced CD3+CD4+ and CD3+CD8+ T cell responses against TEM1 antigen. The CD3+CD8+ T cell response from Tem1-TT–vaccinated mice correlated with suppression of tumor growth. ICS confirmed that Tem1-TT immunization induced an AH1-specific CD3+CD8+ T cell response that also correlated with tumor volume. (B) Splenocytes from mice vaccinated with Tem1-TT recognized TEM1696–710 peptide and the E7 antigen, but not control peptide (TEM1691–705). Only Tem1-TT vaccination was able to induce both a TEM1 and an E7 CD3+CD8+ T cell response, both of which correlated with tumor volume. Correlation analysis was performed by Spearman’s rank correlation.