Tumor infiltrating PD-1+ dendritic cells mediate immune suppression in ovarian cancer

• Published in: The Journal of immunology (1950) 2011-05, Vol.186 (12), p.6905-6913
• Main Authors: Krempski, James, Karyampudi, Lavakumar, Behrens, Marshall D., Erskine, Courtney L., Hartmann, Lynn, Dong, Haidong, Goode, Ellen L., Kalli, Kimberly R., Knutson, Keith L.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1100274

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.