Tumor cells employ various methods of immune suppression to overcome antitumor immunity. One such method is that of programmed death ligand-1 (PD-L1 or B7-H1), which upon binding its receptor programmed death-1 (PD-1) on T cells triggers apoptotic death of the activated T cells. Over-expression of the costimulatory molecule CD80 on PD-L1+ tumor cells, or inclusion of a soluble form of CD80 (CD80-Fc) maintains the activation of PD-1+ activated T cells. Using T cells from CD28-deficient mice and antibodies to block CD28 on human T cells, we now report that a soluble form of CD80 mediates this effect by simultaneously neutralizing the PD-1/PD-L1-mediated immune suppression and by providing CD80-CD28 costimulation. In summary, PD-L1 is a potent mediator of immune suppression that inhibits antitumor immunity in many cancer patients. In this study, we show that a soluble form of the costimulatory molecule CD80 increases the production of IFNγ by PD-1+ activated T cell more effectively than antibodies to PD-1 or PD-L1. Therefore, soluble CD80 may be a more effective therapeutic than these checkpoint antibodies for facilitating the development and maintenance of antitumor immunity because it has the dual functions of preventing PD-L1-mediated immune suppression and simultaneously delivering the second signal for T-cell activation.
- Received November 14, 2013.
- Revision received February 28, 2014.
- Accepted March 19, 2014.
- Copyright © 2014, American Association for Cancer Research.