Figure 2.

Spatiotemporal organization of early versus late stages of tumor-mediated CD8⁺ T cell dysfunction. (A) Naïve CD8⁺ T cell priming against tumor antigen in peripheral LNs (or intratumoral TLS, not depicted) results in the formation of a stem-like PD-1^loCD8⁺ T cell population with self-renewing properties. (B) This population represents an active reservoir of cells that can give rise to effector-like PD-1^loCD8⁺ T_ex after chemokine-mediated trafficking to and positioning within the TME via CCL5 and CXCL9. (C) However, persistent antigen load in the TME eventually forces continued differentiation of these cells into terminally dysfunctional PD-1^hiCD8⁺ T_ex. The PD-1^hi state is accompanied by heightened co-inhibitory receptor expression (including Tim-3, Lag-3, CD160, 2B4, TIGIT, and CTLA-4) and progressive loss of effector functions. Once CD8⁺ T_ex enter a PD-1^hi state, epigenetic enforcement prevents de-differentiation back to functional stem-like and effector-like PD-1^lo states. Anti-tumoral responses facilitated by ICB (e.g., anti-PD-1) arise from expansion from only lymphoid or intratumoral PD-1^loCD8⁺ T_ex subsets. The functionally inferior, ICB-resistant PD-1^hiCD8⁺ T_ex fate ultimately culminates in apoptosis.