PD-1 and BTLA and CD8⁺ T-cell “exhaustion” in cancer

Abstract

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.

Keywords: :

• exhaustion
• cancer
• PD-1
• BTLA
• CD8⁺ T cells
• tumor infiltrating lymphocytes

Grant Support

This work was supported by National Cancer Institute (NCI) grant R01-CA111999 to L.R., by The University of Texas MD Anderson Cancer Center Support Grant (P30-CA16672), and Award No. TL1RR024147 from the National Center for Research Resources to R.W. We also acknowledge support from a Melanoma SPORE Developmental Grant (P50-CA093459-05-DRP21) and a Team Science Award from the Melanoma Research Alliance (MRA) to L.R. Support from the Dr Miriam and Sheldon Adelson Medical Research Foundation (AMRF) and the Mulva Foundation are also greatly appreciated.