PD-1 suppresses the maintenance of cell couples between cytotoxic T cells and target tumor cells within the tumor

The killing of tumor cells by CD8+ T cells is suppressed by the tumor microenvironment, and increased expression of inhibitory receptors, including programmed cell death protein-1 (PD-1), is associated with tumor-mediated suppression of T cells. To find cellular defects triggered by tumor exposure and associated PD-1 signaling, we established an ex vivo imaging approach to investigate the response of antigen-specific, activated effector CD8+ tumor-infiltrating lymphocytes (TILs) after interaction with target tumor cells. Although TIL–tumor cell couples readily formed, couple stability deteriorated within minutes. This was associated with impaired F-actin clearing from the center of the cellular interface, reduced Ca2+ signaling, increased TIL locomotion, and impaired tumor cell killing. The interaction of CD8+ T lymphocytes with tumor cell spheroids in vitro induced a similar phenotype, supporting a critical role of direct T cell–tumor cell contact. Diminished engagement of PD-1 within the tumor, but not acute ex vivo blockade, partially restored cell couple maintenance and killing. PD-1 thus contributes to the suppression of TIL function by inducing a state of impaired subcellular organization.

Source: Signal Transduction Knowledge Environment - September 14, 2020 Category: Science Authors: Ambler, R., Edmunds, G. L., Tan, S. L., Cirillo, S., Pernes, J. I., Ruan, X., Huete-Carrasco, J., Wong, C. C. W., Lu, J., Ward, J., Toti, G., Hedges, A. J., Dovedi, S. J., Murphy, R. F., Morgan, D. J., Wülfing, C. Tags: STKE Research Articles Source Type: news