4-1BB costimulation promotes bystander activation of human CD8 T cells.

Costimulatory signals potently promote T-cell proliferation and effector function. Agonistic antibodies targeting costimulatory receptors of the TNFR family, such as 4-1BB and CD27, have entered clinical trials in cancer patients. Currently there is limited information how costimulatory signals regulate antigen-specific but also bystander activation of human CD8 T cells. Engineered antigen presenting cells (eAPC) efficiently presenting several common viral epitopes on HLA-A2 in combination with MHC class I tetramer staining were used to investigate the impact of costimulatory signals on human CD8 T-cell responses. CD28 costimulation potently augmented the percentage and number of antigen-reactive CD8 T cells, whereas eAPC expressing 4-1BB-ligand induced bystander proliferation of CD8 T cells and massive expansion of NK cells. Moreover, the 4-1BB agonist urelumab similarly induced bystander proliferation of CD8 T cells and NK cells in a dose-dependent manner. However, the promotion of bystander CD8 T-cell responses is not a general attribute of costimulatory TNF receptor superfamily (TNFRSF) members, since CD27 signals enhanced antigen-specific CD8 T cells responses without promoting significant bystander activation. Thus, the differential effects of costimulatory signals on the activation of human bystander CD8 T cells should be taken into account when costimulatory pathways are harnessed for cancer immunotherapy.