Endothelin B Receptor, a New Target in Cancer Immune Therapy

Abstract

The endothelins and their G protein-coupled receptors A and B have been implicated in numerous diseases and have recently emerged as pivotal players in a variety of malignancies. Tumors overexpress the endothelin 1 (ET-1) ligand and the endothelin-A-receptor (ET A R). Their interaction induces tumor growth and metastasis by promoting tumor cell survival and proliferation, angiogenesis, and tissue remodeling. On the basis of results from xenograft models, drug development efforts have focused on antagonizing the autocrine-paracrine effects mediated by ET-1/ET A R. In this review, we discuss a novel role of the endothelin-B-receptor (ET B R) in tumorigenesis and the effect of its blockade during cancer immune therapy.We highlight key characteristics of the B receptor such as its specific overexpression in the tumor compartment; and specifically, in the tumor endothelium, where its activation by ET-1suppressesT-cell adhesion and homing to tumors. We also review our recent findings on the effects of ET B R-specific blockade in increasing T-cell homing to tumors and enhancing the efficacy of otherwise ineffective immunotherapy.

CARs on the Highway: Chimeric Antigen Receptor Modified T Cells for the Adoptive Cell Therapy of Malignant Diseases

“…Extensively amplified CAR T cells often express an altered panel of chemokine receptors; transgenic co-expression of chemokine receptors can enforce specific trafficking, for example, transgenic CXCR2 (CXCL1 receptor) improves trafficking to melanoma [89] and CCR2b to neuroblastoma [90]. On the other hand, blocking of migration inhibitory receptors like endothelin-B receptor improves T cell infiltration into the tumor lesion [91]. Targeting vascular endothelial growth factor (VEGF) receptor-2, which is over-expressed by tumor endothelial cells, improves vascular evasion of CARs on the Highway: Chimeric Antigen Receptor Modified T Cells for the Adoptive Cell Therapy of Malignant Diseases http://dx.doi.org/10.5772/66496 CAR T cells [92].…”

Modulation of Tumor Angiogenesis by a Host Anti-Tumor Response in Colorectal Cancer

“…The endothelin (ET) family comprises four members designated ET-1 to -4 (Kandalaft et al, 2009). ETs derive from precursor proteins after cleavage by membrane-bound metalloproteinases.…”

“…ETs derive from precursor proteins after cleavage by membrane-bound metalloproteinases. ET-1 is the most potent ligand and the most widely expressed in endothelial cells (Kandalaft et al, 2009). In addition, ET-1 is overexpressed in many tumor cell lines and many tumors, including CRC (Kusuhara et al, 1990;Arun et al, 2004;Bagnato & Rosano, 2008).…”

“…In addition, ET-1 is overexpressed in many tumor cell lines and many tumors, including CRC (Kusuhara et al, 1990;Arun et al, 2004;Bagnato & Rosano, 2008). Two endothelin receptors have been identified: the endothelin A and the endothelin B receptor, respectively ET A R and ET B R (Kandalaft et al, 2009). In normal tissues, ET A R and ET B R regulate vasoconstriction and are also involved in inflammation.…”

“…In particular, ET A R promote T-cell adhesion to endothelial cells, whereas ET B R inhibits it. In tumor cells, concomitant up-regulation of ET-1 and ET A R inhibits apoptosis and promotes cell proliferation, invasion and metastasis (Kedzierski & Yanagisawa, 2001;Kandalaft et al, 2009). In a study comparing the expression profiles of tumor associated endothelial cells (TECs) in ovarian cancer with or without TILs, ET B R has been associated with the absence of TILs and short patient survival time (Buckanovich et al, 2008).…”