Abstract B017: A soluble form of CD80 inhibits PD-L1 immune suppression and stimulates T cells through CD28-specific pathways indicating potential for increased therapeutic activity over checkpoint inhibition alone

Abstract

Abstract Antibodies that block the PD-1/PD-L1 pathway have demonstrated therapeutic success against several cancer types, but do not induce a response in the majority of patients. The development of treatments that provide activation signals to T cells by targeting co-stimulatory receptors, in addition to checkpoint inhibition, may increase anti-tumor immunity and the percent of responding patients. CD80/B7-1 is a co-stimulatory molecule that also interacts with PD-L1. CD80 is expressed by antigen presenting cells and ligates to CD28 providing co-stimulation during T cell activation. Furthermore, PD-L1 interacts with T cell CD80 in a reverse signaling pathway that promotes T cell anergy. The ability of CD80 to block inhibitory and promote stimulatory signaling pathways in T cell activation suggests potential therapeutic value. We have shown that soluble CD80 fused to the Fc region of IgG (CD80-Fc) blocks PD-1/PD-L1 interactions thus restoring activation of CD4+ and CD8+ T cells. Moreover, CD80-Fc was more effective in vitro than PD-1/PD-L1 monoclonal antibodies at restoring T cell activation, which suggests that CD80-Fc may be stimulating CD28 in addition to blocking PD-1/PD-L1 signaling. Stimulation of T cell CD28 in the absence of other signals induces downstream transcription, and signaling pathway activation. In fact, agonist CD28 antibody can induce functions in T cells in both naïve and activated cells, even in the absence of TCR activation. We now demonstrate that CD80-Fc does indeed stimulate T cells via CD28 activation by demonstrating comparable downstream results of CD80-Fc and agonist CD28 antibody treatment of both human and mouse T cells. Therefore, CD80-Fc may provide a novel therapeutic approach to target T cell checkpoint inhibition in addition to providing stimulatory signaling to improve T cell activation and anti-tumor immunity. Citation Format: Tiha M. Long, Suzanne Ostrand-Rosenberg. A soluble form of CD80 inhibits PD-L1 immune suppression and stimulates T cells through CD28-specific pathways indicating potential for increased therapeutic activity over checkpoint inhibition alone. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B017.