Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer

J Duraiswamy, GJ Freeman, G Coukos - Cancer research, 2013 - AACR
J Duraiswamy, GJ Freeman, G Coukos
Cancer research, 2013AACR
The tumor microenvironment mediates induction of the immunosuppressive programmed
cell death-1 (PD-1) pathway, and targeted interventions against this pathway 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 …
Abstract
The tumor microenvironment mediates induction of the immunosuppressive programmed cell death-1 (PD-1) pathway, and targeted interventions against this pathway 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 (TIL) correlated with expression of PD-1 ligands by tumor cells and tumor-derived myeloid cells, including tumor-associated macrophages (TAM), dendritic cells, and myeloid-derived suppressor cells (MDSC). When combined with GVAX or FVAX vaccination (consisting of irradiated ID8 cells expressing granulocyte macrophage colony—stimulating factor or FLT3 ligand) and costimulation by agonistic α-4-1BB 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 regulatory T cells (Treg) 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. Cancer Res; 73(23); 6900–12. ©2013 AACR.
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