Proinflammatory activity of VEGF-targeted therapy via tumour endothelial cell anergy reversal

Ongoing angiogenesis renders the tumour endothelium resistant to inflammatory cytokines and interferes with leukocyte adherence, resulting in immune escape. Tumor endothelial cell anergy is the name given to this phenomenon. We wanted to see if anti-angiogenic drugs might overcome endothelial cell anergy and create pro-inflammatory circumstances.

RNAseq and immunohistochemistry characterization of the leukocyte infiltration were performed on tissues from renal cell cancer (RCC) patients treated with VEGF pathway-targeted medicines and control tissues. The modulation of adhesion molecules in cultured endothelial cells, a preclinical model, and human tissues was studied and linked with leukocyte infiltration.

It has been demonstrated that treating RCC patients with sunitinib or bevacizumab overcomes tumour endothelial cell anergy. This therapy caused the tumour to become more inflammatory, as evidenced by increased infiltration of all major leukocyte subsets, including T cells, regulatory T cells, M1- and M2-like macrophages, and activated dendritic cells. In vitro, anti-angiogenic medicines restored ICAM-1 expression in angiogenic endothelial cells. A panel of tyrosine kinase inhibitors was also demonstrated to promote transendothelial migration of non-adherent and monocytic leukocytes.

ICAM-1 expression was observed to be considerably enhanced in both the sunitinib and bevacizumab-treated groups of RCC patients' initial tumours. Following VEGF-targeted therapy, genomic research showed the link between enhanced immune cell infiltration and ICAM-1 expression.

The findings back up the increasing idea that anti-angiogenic treatment might increase immunity and demonstrate how immunotherapy techniques can benefit from being combined with anti-angiogenic drugs.