The host protecting the tumor from the host - targeting PD‑L1 expressed by host cells

Abstract

Tumors frequently escape from immune surveillance by hijacking the natural control mechanisms that regulate normal immune responses. The programmed death-1 receptor (PD‑1) on T cells normally helps limit excessive immune activation, but it can also suppress beneficial antitumor immunity. In the clinic, blocking either PD‑1 or one of its principal counterligands, programmed death-ligand 1 (PD‑L1), can lead to dramatic responses in certain patients. Because PD‑L1 can be expressed by both the tumor cells themselves and also the host cells, including host immune cells, the actual mechanistic target of therapy has remained unclear. In the current issue of the JCI, two papers, one by Tang and colleagues and the other by Lin and colleagues, used a variety of mouse tumor models to demonstrate that the relevant target for therapy in each case was the PD‑L1 molecules expressed by host cells and not by tumor cells. If this finding is generalized to humans, then it would suggest that the tumor persuades the host to actively suppress its own attempted immune response against the tumor cells.

Figure 1. Possible locations for the immunosuppressive PD‑L1 targeted by checkpoint blockade.

Four different hypothetical models are presented, along with the sites in which PD‑L1 might be active, either in tumor or TDLN. (A) The traditional model, in which PD‑L1 is expressed on the tumor cell itself and directly inhibits killing of the target cell by activated PD‑1⁺ effector T cells. (B) Model in which inhibitory PD‑L1 is expressed on DCs during the initial priming of naive tumor-specific T cells. (C) Indirect model in which PD‑L1 delivers an activating signal to Tregs via PD‑1 and the activated Tregs then mediate immune suppression. (D) Model in which DCs in tumor or TDLNs constantly interact with mature, exhausted effector T cells and PD‑L1 serves to inhibit reactivation driven by B7-CD28 costimulation. In the figure, PD‑L1 is depicted as being expressed on the same DC that could reactivate the exhausted T cell, but this interaction might also occur in trans (PD‑L1 might be expressed on a neighboring macrophage or other APC).