PD-1 and BTLA and CD8(+) T-cell “exhaustion” in cancer: “Exercising” an alternative viewpoint

The elevated expression of PD-1, BTLA, and other co-inhibitory molecules on T cells from cancer patients has become an accepted signature for a state called T-cell “exhaustion” that has emerged almost as dogma in the field. However, here we propose that in some cases this “exhausted” T-cell phenotype may instead be an indicator of T cells that are in a more heightened state of T-cell activation more susceptible to negative regulation rather than being “exhausted.” This alternative interpretation fits in line with the view that CD8(+) T-cell activation in cancer results from a continuum of signals regulating their differentiation towards potent effector cells.