Therapeutic PD-1 Pathway Blockade Augments with other Modalities of Immunotherapy to Prevent Immune Decline in Ovarian Cancer
Menée à l'aide d'un modèle murin de cancer épithélial de l'ovaire, cette étude met en évidence des mécanismes par lesquels des anticorps anti PD1 ou PD-L1 renforcent l'efficacité de mécanismes immunitaires antitumoraux
The tumor microenvironment mediates induction of the immunosuppressive programmed death-1 (PD-1) pathway, targeted interventions against which can help restore antitumor immunity. To gain insight into these responses, we studied the interaction between PD-1 expressed on T cells and its ligands (PD-1:PD-L1, PD-1:PD-L2, and PD-L1:B7.1) expressed on other cells in the tumor microenvironment, using a syngeneic orthotopic mouse model of epithelial ovarian cancer (ID8). Exhaustion of tumor-infiltrating lymphocytes (TILs) correlated with expression of PD-1 ligands by tumor cells and tumor-derived myeloid cells, including macrophages (TAM), dendritic cells (DC) and myeloid-derived suppressor cells (MDSC). When combined with GVAX or FVAX vaccination (consisting of irradiated ID8 cells expressing GM-CSF or FLT3 ligand) and co-stimulation by agonistic α4-1BB or TLR 9 ligand, antibody mediated blockade of PD-1 or PD-L1 triggered rejection of ID8 tumors in 75% of tumor-bearing mice. This therapeutic effect was associated with increased proliferation and function of tumor antigen-specific effector CD8+ T cells, inhibition of suppressive T regulatory cells (Tregs) and MDSC, upregulation of effector T cell signaling molecules and generation of T memory precursor cells. Overall, PD-1/PD-L1 blockade enhanced the amplitude of tumor immunity by reprogramming suppressive and stimulatory signals that yielded more powerful cancer control.