A Soluble Form of CD80 Enhances Antitumor Immunity by Neutralizing Programmed Death Ligand-1 and Simultaneously Providing Costimulation

Tumor cells use various methods of immunosuppression to overcome antitumor immunity. One such method is that of programmed death ligand-1 (PD-L1 or B7-H1), which upon binding its receptor PD-1 on T cells triggers apoptotic death of the activated T cells. Overexpression 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 PD-1-PD-L1-mediated immunosuppression and by providing CD80-CD28 costimulation, and is more effective than antibodies to PD-L1 or PD-1 in maintaining IFN gamma production by PD-1(+) activated T cells. 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 immunosuppression and simultaneously delivering the second signal for T-cell activation. (C) 2014 AACR.