Figure 3
From: T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy
Native homing circuitry for Teff (CD8+) cell entry into melanoma and other lesional tissues. Melanoma-infiltrating Teff cells natively express homing molecules at variable and suboptimal levels, including E-selectin ligands, VLA-4 and LFA-1 integrins, CXCR3 and CCR5-chemokine receptors, along with a TCR specific for a melanoma antigen. (Step 1) Circulating Teff cells tether and roll in blood flow via engagement of undefined E-selectin ligands (synthesized by α1,3FT) with tumor endothelial E-selectin. This interaction slows Teff cell velocity, thereby prepping Teff cells for step 2. (Steps 2–3) Chemokines CXCL9, CXCL10, CCL3, CCL4, and CCL5 are secreted directly by melanoma and/or stromal cells of the tumor microenvironment and then bound by Teff cell-CXCR3 and CXCR5 receptors. Chemokines may be concentrated on GAGs expressed on tumor microvessel apical, basal, or basement membrane surfaces for enhanced chemokine receptor binding. CXCR3/CCR5-chemokine ligation elicits Gαi-signaling, switches VLA-4 from an intermediate to highly active structure and LFA-1 from inactive to highly active, and eventuates in VLA-4/VCAM-1 and LFA-1/ICAM-1-mediated firm adhesion (arrows; solid=known signaling, dotted=speculated signaling). Integrins may also undergo activation independently of chemokine receptor signaling via a ‘step 2 bypass’ circuit involving bimolecular association of E-selectin ligands directly with VLA-4 (arrow). (Step 4) Firmly adherent Teff cells undergo VLA-4/LFA-1 and CXCR3/CCR5-mediated transendothelial migration and directly contact heterogeneous tumor cell subsets, including malignant melanoma-initiating stem (MMIC) and non-stem subsets, via TCR-based recognition of melanoma antigens displayed on HLA. Accessory homing mediators supporting Teff cell infiltration into melanoma (boxed, no question marks) or other cancer types (boxed, question marks) are listed. Question marks indicate determinants which might be employed in Teff cell trafficking into melanoma though for which direct data is lacking. Also listed are various blood and lymphatic channels that traverse the tumor parenchyma to provide access routes for circulating Teff cells, including peritumoral and angiogenic vessels, vasculogenic mimicry channels, ectopic lymphoid venules, and lymphatic venules.
