1. Homing to solid cancers: a vascular checkpoint in adoptive cell therapy using CAR T-cells
- Author
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Ager, Ann, Watson, H. Angharad, Wehenkel, Sophie C., and Mohammed, Rebar N.
- Subjects
selectins ,T-Lymphocytes ,chemokine receptors ,Chimeric Antigen Receptor Therapy in Haematology and Oncology: Current Successes and Challenges ,tumouricidal T-lymphocytes ,high endothelial venules ,tumour blood vessels ,Adoptive Transfer ,S4 ,endothelial cell anergy ,Mice ,Neoplasms ,integrins ,Animals ,Humans ,homing ,Biochemical Society Focused Meetings ,extravasation ,vessel normalization - 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.
- Published
- 2016