title: Homing to solid cancers: a vascular checkpoint in adoptive cell therapy using CAR T-cells.
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.
authors.affiliation: Systems Immunity University Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, CF14 4XN, U.K. agera@cardiff.ac.uk.
authors.forename: Ann
authors.initials: A
authors.lastname: Ager
authors.affiliation: Systems Immunity University Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, CF14 4XN, U.K.
authors.forename: H Angharad
authors.initials: HA
authors.lastname: Watson
authors.affiliation: Systems Immunity University Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, CF14 4XN, U.K.
authors.forename: Sophie C
authors.initials: SC
authors.lastname: Wehenkel
authors.affiliation: Systems Immunity University Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, CF14 4XN, U.K.
authors.forename: Rebar N
authors.initials: RN
authors.lastname: Mohammed
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology*
keywords: chemokine receptors; endothelial cell anergy; extravasation; high endothelial venules; homing; integrins; selectins; tumour blood vessels; tumouricidal T-lymphocytes; vessel normalization