TY - JOUR
T1 - Tumor-infiltrating programmed death receptor-1+ dendritic cells mediate immune suppression in ovarian cancer
AU - Krempski, James
AU - Karyampudi, Lavakumar
AU - Behrens, Marshall D.
AU - Erskine, Courtney L.
AU - Hartmann, Lynn
AU - Dong, Haidong
AU - Goode, Ellen L.
AU - Kalli, Kimberly R.
AU - Knutson, Keith L.
PY - 2011/6/15
Y1 - 2011/6/15
N2 - Within the ovarian cancer microenvironment, there are several mechanisms that suppress the actions of antitumor immune effectors. Delineating the complex immune microenvironment is an important goal toward developing effective immune-based therapies. A dominant pathway of immune suppression in ovarian cancer involves tumor-associated and dendritic cell (DC)-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, programmed death receptor-1 (PD-1), is also expressed on myeloid cells, complicating interpretations of how B7-H1 regulates 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 + DCs 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 DCs suppressed NF-κB activation, release of immune regulatory cytokines, and upregulation of costimulatory molecules. PD-1 blockade in mice bearing ovarian cancer substantially reduced tumor burden and increased effector Ag-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.
AB - Within the ovarian cancer microenvironment, there are several mechanisms that suppress the actions of antitumor immune effectors. Delineating the complex immune microenvironment is an important goal toward developing effective immune-based therapies. A dominant pathway of immune suppression in ovarian cancer involves tumor-associated and dendritic cell (DC)-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, programmed death receptor-1 (PD-1), is also expressed on myeloid cells, complicating interpretations of how B7-H1 regulates 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 + DCs 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 DCs suppressed NF-κB activation, release of immune regulatory cytokines, and upregulation of costimulatory molecules. PD-1 blockade in mice bearing ovarian cancer substantially reduced tumor burden and increased effector Ag-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.
UR - http://www.scopus.com/inward/record.url?scp=79959549102&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79959549102&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1100274
DO - 10.4049/jimmunol.1100274
M3 - Article
C2 - 21551365
AN - SCOPUS:79959549102
SN - 0022-1767
VL - 186
SP - 6905
EP - 6913
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -