Homing to solid cancers: a vascular checkpoint in adoptive cell therapy using CAR T-cells. (11th April 2016)

• Record Type: Journal Article
• Authors: Ager, Ann; Watson, H. Angharad; Wehenkel, Sophie C.; Mohammed, Rebar N.
• Is Part Of: Biochemical Society transactions. Volume 44:Number 2(2016)
• Page Start: 377
• Page End: 385
• Publication Date: 2016-04-11
• Subjects: chemokine receptors -- endothelial cell anergy -- extravasation -- high endothelial venules -- homing -- integrins -- selectins -- tumour blood vessels -- tumouricidal T-lymphocytes -- vessel normalization; Biochemistry -- Congresses; 572
• DOI: 10.1042/BST20150254
• Languages: English
• ISSNs: 0300-5127

Abstract

Abstract : 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.