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.

Measurement and Quantitative Characterization of Whole-Body Pharmacokinetics of Exogenously Administered T Cells in Mice

“…The process of T cell disposition is complex and depends on multiple stimuli-dependent steps such as rolling and adhesion on vascular endothelial cells, chemokine-driven extravasation, and margination to specific tissues (Hogg, 1993;Springer, 1994;Girard and Springer, 1995). This process is further complicated by dynamic regulation of cell adhesion molecules expressed on tissues and changes in cell surface phenotype based on the nature of the T cell (Defilippi et al, 1993;Ager et al, 2016).…”

Mucosal Immunity in the Female Murine Mammary Gland

“…The mechanism of how memory CD4 + T cells are recruited during involution is unknown, although activated vasculature may be predicted (58). Indeed, mammary vasculature is highly dynamic across a reproductive cycle (59,60) and could play a role in differential recruitment and drainage of immune cells.…”

T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy

“…9,134 These vessels may be present either peripheral to (peritumoral) or formed de novo within (angiogenic) tumor cores. Since surrounding peritumoral vessels may be derived from already pre-existing normal endothelium prior to tumorigenesis, they often better resemble the vasculature of normal tissues.…”

“…133,134,153 Destabilization of intratumoral vessel integrity may ensue from dense, overlaying lesional tissue, which can create biomechanical tension and alter blood flow. 133 These tumor-intrinsic microvessels, often detected with mAbs against platelet-endothelial cell adhesion molecule-1 (PECAM-1), generally express low to nil E-selectin, P-selectin, ICAM-1/2, VCAM-1, MadCAM-1, or VAP-1 as has been observed in metastatic melanomas, squamous cell carcinomas (SCCs) and/or tumors of various origin, thereby hindering leukocyte binding, homing and entry into the tumor core.…”