Tumour immunotherapy: Little pig, little pig, let me come in

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When the endothelin B receptor (ETBR) is highly expressed in the tumor endothelium it blocks T-cell homing, suggesting that pharmacologic inhibition of ETBR might cause immunotherapy-induced T cells to gain access to the tumor.

With all its huffing and puffing, the nursery rhyme wolf could not blow down the little pigs' house made of bricks. The wall of endothelial cells surrounding tumour-associated blood vessels can be equally impenetrable, preventing T cells from exiting the blood and destroying the tumour. A recent study in Nature Medicine identifies a new mechanism by which the tumour endothelium blocks T-cell homing and describes how this can be overcome to enhance the efficacy of tumour immunotherapy.

To understand how the tumour endothelium might regulate T-cell homing, the authors compared gene expression by tumour endothelial cells (TECs) from human ovarian cancers with and without tumour-infiltrating lymphocytes (TILs). Numerous genes were found to be differentially expressed; of particular interest to the authors was endothelin B receptor (ETBR), which was expressed at higher levels by TECs from tumours lacking TILs than those with TILs.

The ligand for ETBR, endothelin-1, is known to be produced at high levels by ovarian cancer cells and has a crucial role in regulating vascular homeostasis and permeability. Indeed, in an in vitro assay, the presence of endothelin-1 inhibited T-cell adhesion to endothelial cells (a step required for lymphocytes to migrate out of the bloodstream). However, the effect of endothelin-1 on adhesion could be neutralized by addition of the specific ETBR inhibitor BQ-788. Further studies showed that the endothelin-1–ETBR interaction suppressed T-cell adhesion by inhibiting the upregulation of expression and clustering of intercellular adhesion molecule 1 (ICAM1) on the endothelium and that nitric-oxide release was required for this effect. Accordingly, the presence of BQ-788 restored ICAM1 expression and reduced nitric-oxide release, thereby facilitating T-cell adhesion to endothelial cells in vitro.

Next, the authors tested whether ETBR blockade by BQ-788 might have a beneficial effect on T-cell homing in mouse models of cancer and improve the efficacy of otherwise ineffective tumour immunotherapy protocols. In the two mouse models studied, systemic antitumour T-cell responses were induced by tumour vaccines (a tumour-cell-based vaccine and a DNA vaccine), but this did not delay the growth of inoculated tumour cells or prolong survival of the mice. However, when the vaccinated mice were treated with BQ-788, tumour growth was delayed and mouse survival increased. This beneficial effect of ETBR blockade by BQ-788 was shown to be the result of increased homing of tumour-specific T cells to the tumour and not due to the induction of higher numbers or activation of these cells.

So, overriding the tumour-induced barrier function of the endothelium with pharmacological inhibitors, such as BQ-788, could prove to be a useful strategy to ensure that tumour-specific T cells that are induced in immunotherapeutic protocols gain sufficient access to the tumour.

Lucy Bird

References

Buckanovich, R. J. et al. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nature Med. 14, 28–36 (2008) | Article | PubMed |
Kershaw, M. H. Opening the gateway to tumors. Nature Med. 14, 13–14 (2008) | Article | PubMed |