Fig. 2

Critical anatomical and microenvironmental waypoints dictating success of CD8⁺ T cell infiltration. (A) TDLNs are the ideal venue for tumour antigen-bearing migratory DCs from the TME to condition the T_H and CD8⁺ T cells. The migratory DCs also pass on the antigens and TME cues to their resident counterparts. With provision of the primary, costimulatory, and cytokine signals by the DCs and T_H sans the inhibitory TME elements, CD8⁺ T cells have the privilege of remaining in the stem-like states and serving as a reservoir of tumour-repressive cells. Establishment of metastases in the LNs demolishes the supportive context for these population-sustaining CD8⁺ T cells. (B) Tumour-associated vascular endothelium is a major barrier against T cell infiltration. Endothelial expression of FasL can precipitate direct CD8⁺ T cell death. Aberrant adhesion molecule expression secondary to VEGF-induced endothelial cell anergy renders it impregnable to CD8⁺ T cells. Tumour-associated high endothelial venules are important sites for CD8⁺ T cell extravasation and aggregation. (C) CAFs orchestrate the tumour-associated stroma and mediate T cell exclusion in a multitude of ways, as illustrated. The APC niches and TLSs are on-site powerhouses that harbour stem-like CD8⁺ T cells and, by safeguarding their survival, greatly amplifies anti-tumour immunity. Conversion to the more terminally differentiated phenotypes ensues the longer the dwell time and the closer the distance to the tumour cells, which are known to foment an immunosuppressive aura.