Dendritic cells (DCs) play a pivotal role in the tumor microenvironment (TME), the latter of which is known to affect disease progression in many human malignancies. Infiltration by mature, active DCs into the tumors confers an increase in immune activation and recruitment of disease-fighting immune effector cells and pathways. DCs are the preferential target of infiltrating T cells. Tumor cells, however, have means of suppressing DC function or of altering the TME in such a way that immune suppressive DC are recruited. Advances in understanding these changes have led to promising developments in cancer therapeutic strategies targeting tumor-infiltrating DCs in order to subdue their immunosuppressive functions and enhance their immune stimulatory capacity.

Within the ovarian cancer microenvironment there are several mechanisms that suppress the actions of anti-tumor immune effectors. Delineating the complex immune microenvironment is an important goal towards developing effective immune-based therapies. A dominant pathway of immune suppression in ovarian cancer involves tumor-associated and dendritic cell-associated, B7-H1. The interaction of B7-H1 with PD-1 on tumor-infiltrating T cells is a widely cited theory of immune suppression involving B7-H1 in ovarian cancer. Recent studies suggest that the B7-H1 ligand, PD-1, is also expressed on myeloid cells complicating interpretations of how B7-H1 regulates dendritic cell (DC) function in the tumor. In this study we found that ovarian cancer-infiltrating DCs progressively expressed increased levels of PD-1 over time in addition to B7-H1. These dual-positive PD-1+B7-H1+ DCs have a classical DC phenotype (i.e. CD11c+CD11b+CD8−) but are immature, suppressive and respond poorly to danger signals. Accumulation of PD-1+B7-H1+ DC in the tumor was associated with suppression of T cell activity and decreased infiltrating T cells in advancing tumors. T cell suppressor function of these DCs appeared to be mediated by T cell associated PD-1. In contrast, ligation of PD-1 expressed on the tumor-associated DC suppressed NFκB activation, release of immune regulatory cytokines, and upregulation of co-stimulatory molecules. PD-1 blockade in mice bearing ovarian cancer substantially reduced tumor burden and increased effector antigen-specific T cell responses. Our results reveal a novel role of tumor infiltrating PD-1+B7-H1+ DCs in mediating immune suppression in ovarian cancer.

Ligation of PD-1 in the tumor microenvironment is known to inhibit effective adaptive anti-tumor immunity. Blockade of PD-1 in humans has resulted in impressive, durable regression responses in select tumor types. However, durable responses have been elusive in ovarian cancer patients. PD-1 was recently shown to be expressed on and thereby impair the functions of tumor-infiltrating murine and human myeloid dendritic cells (TIDC) in ovarian cancer. In the present work, we characterize the regulation of PD-1 expression and the effects of PD-1 blockade on TIDC. Treatment of TIDC and bone marrow-derived DC with IL-10 led to increased PD-1 expression. Both groups of DC also responded to PD-1 blockade by increasing production of IL-10. Similarly, treatment of ovarian tumor-bearing mice with PD-1 blocking antibody resulted in an increase in IL-10 levels in both serum and ascites. While PD-1 blockade or IL-10 neutralization as monotherapies were inefficient, combination of these two led to improved survival and delayed tumor growth; this was accompanied by augmented anti-tumor T and B cell responses and decreased infiltration of immunosuppressive MDSC. Taken together, our findings implicate compensatory release of IL-10 as one of the adaptive resistance mechanisms that undermine the efficacy of anti-PD-1 (or anti-PD-L1) monotherapies and prompts further studies aimed at identifying such resistance mechanisms.