Homing to solid cancers: a vascular checkpoint in adoptive cell therapy using CAR T-cells

• Published in: Biochemical Society transactions Vol. 44; no. 2; p. 377
• Main Authors: Ager, Ann, Watson, H Angharad, Wehenkel, Sophie C, Mohammed, Rebar N
• Format: Journal Article
• Language: English
• Published: England 15.04.2016
• Subjects: Adoptive Transfer; Animals; Humans; Mice; Neoplasms - therapy; T-Lymphocytes - immunology; extravasation; chemokine receptors; integrins; vessel normalization; tumour blood vessels; selectins; tumouricidal T-lymphocytes; homing; endothelial cell anergy; high endothelial venules
• ISSN: 1470-8752
• DOI: 10.1042/BST20150254

The success of adoptive T-cell therapies for the treatment of cancer patients depends on transferred T-lymphocytes finding and infiltrating cancerous tissues. For intravenously transferred T-cells, this means leaving the bloodstream (extravasation) from tumour blood vessels. In inflamed tissues, a key event in extravasation is the capture, rolling and arrest of T-cells inside blood vessels which precedes transmigration across the vessel wall and entry into tissues. This depends on co-ordinated signalling of selectins, integrins and chemokine receptors on T-cells by their respective ligands which are up-regulated on inflamed blood vessels. Clinical data and experimental studies in mice suggest that tumour blood vessels are anergic to inflammatory stimuli and the recruitment of cytotoxic CD8(+)T-lymphocytes is not very efficient. Interestingly, and somewhat counter-intuitively, anti-angiogenic therapy can promote CD8(+)T-cell infiltration of tumours and increase the efficacy of adoptive CD8(+)T-cell therapy. Rather than inhibit tumour angiogenesis, anti-angiogenic therapy 'normalizes' (matures) tumour blood vessels by promoting pericyte recruitment, increasing tumour blood vessel perfusion and sensitizing tumour blood vessels to inflammatory stimuli. A number of different approaches are currently being explored to increase recruitment by manipulating the expression of homing-associated molecules on T-cells and tumour blood vessels. Future studies should address whether these approaches improve the efficacy of adoptive T-cell therapies for solid, vascularized cancers in patients.