Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy

Nat Med. 14(1):28-36, 2008

Speaker: 林怡璇                          Date: 2008/03/12 13:10~14:00

Commentator: 張堯 老師                   Place: Room 601

Abstract:

    To date, cancer vaccines remain ineffective. The mechanisms underlying these failures remain unclear, but factors in the tumor microenvironment may be involved. The authors have previously reported that intraepithelial tumor-infiltrating lymphocytes (TILs) are detected in fewer than half of individuals with ovarian cancer, and individuals with intraepithelial TILs have markedly improved survival^[1]. In this article, the authors first compared tumor endothelial cell (TEC) profiles from tumors with or without intraepithelial TILs using transcriptional profiling of microdissected TECs from human ovarian cancers. They found overexpression of specific endothelial molecule, endothelin B receptor (ET_BR), was associated with the absence of TILs and short patient survival time. ET_BR has a crucial role in vascular homeostasis, and its ligand endothelin-1(ET-1) expresses at high level by ovarian cancer cells in vivo ^[2]. The authors further studied the role of ET_BR in tumors with the absence of TILs. The results showed that ET_BR inhibitor, BQ-788, increases T cell adhesion due to nitric oxide (NO) blockade of the endothelium which would upregulate and relocalize intercellular adhesion molecule-1 (ICAM-1). Finally, they investigated the therapeutic value of ET_BR blockade by animal model. They found that ET_BR blockade only could not cure mice with tumors, suggesting that inhibiting ET_BR was in itself not sufficient. However, specific blockade of ET_BR potentially augments the efficacy of tumor vaccines in vivo by T cells homing to tumors, and which would not increase the number or activate of systemic tumor-reactive T cells. In conclusion, these findings highlight a molecular mechanism with the potential to be pharmacologically manipulated to enhance the efficacy of tumor immunotherapy in humans.

References:

1.          Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203-213 (2003).

2.          Bagnato, A. et al. Emerging role of the endothelin axis in ovarian tumor progression. Endocr. Relat. Cancer 12, 761-772 (2005)