Activating Anti-tumor Immunity by Overcoming Programmed Death Ligand 1-mediated Immunosuppression

Immunotherapy is a promising approach for the treatment of primary and metastatic cancer because of the immune system's ability to recognize and target tumor cells. Tumor cells employ various mechanisms to escape anti-tumor immunity. One such mechanism they employ is mediated by programmed death ligand 1 (PDL1), which interacts with T cell-expressed PD1 and results in T cell apoptosis. PDL1 is expressed constitutively or is induced by interferon-gamma (IFNγ) on the surface of most tumor cells and protects tumor cells from T cell-mediated lysis. PDL1 also suppresses T cell activation by binding T cell-expressed CD80. Given that CD80 and PDL1 bind each other, work in this thesis will exploit this interaction to design a therapy that prevents PDL1-mediatied immunosuppression to allow tumor recognition by tumor-specific T cells. Therefore, it was hypothesized that overexpressing CD80 on PDL1+ tumor cells will functionally inactivate PDL1, and secondly that a soluble form of CD80 (CD80-Fc) would similarly inactivate PDL1. Initial experiments demonstrated that co-expression of CD80 by PDL1+ mouse and human tumor cells prevented the binding of PD1, and co-culture of CD80+PDL1+ tumor cells with PD1+ T cells maintained T cells in an activated state. Further work demonstrated that CD80-Fc restores activation of CD4+ and CD8+ T cells similar to that of membrane-bound CD80. Since monoclonal antibodies to PD1 and PDL1 are currently in clinical trials, the ability of CD80-Fc to prevent PDL1-mediated suppression was compared to that of anti-PDL1 and anti-PD1 antibodies. These experiments demonstrated that CD80-Fc is more effective at facilitating T cell activation than treatment with mAb to either PD1 or PDL1. Although CD80 is well known as a costimulatory molecule, using antibodies to block CD28-CD80 costimulation on T cells does not prevent CD80-mediated restoration of T cell activation, indicating an alternate role for CD80. In the absence of costimulation, CD80-Fc restores T cell activation, confirming that soluble CD80 mediates this effect by simultaneously neutralizing PD1-PDL1-mediated immune suppression and providing CD28-CD80 costimulation. These studies identify a new role for CD80 and suggest that it may be a better therapeutic agent than antibody therapy for overcoming PD1-PDL1-mediated immune suppression in cancer patients