Tumor plasmacytoid dendritic cells and tumor immunity

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DESCRIPTION (provided by applicant): Although most cancers possess tumor-associated antigens (TAA) that can serve as targets of the immune system, immunity is not effectively induced in most tumor-bearing hosts. Dysregulation of dendritic cell (DC) differentiation, function and trafficking may contribute to tumor immunopathogenesis. Malignant ascites contains viable tumor and immune cells, which we used as a model for the tumor environment. We identified a significant population of PDC, not MDC, in malignant ascites of patients with ovarian carcinoma. Our work demonstrate that tumor PDC induce TAA-specific IL-10+CCR7+CD8+ T cells. These T cells migrate with lymphoid homing molecule CCR7, and suppress MDC mediated TAA-specific protective tumor immunity. Further, MDC cannot recover the suppressive effects. More importantly, we show that tumor-mediated upregulation of PDC B7-H1 contributes to detrimental immunity induced by tumor PDC. We now extend these observations, and further demonstrate in detail the nature of TAA-specific T cell immunity induced by tumor PDC, and the underlying mechanisms. There exists a significant amount of PDC in tumor ascites. Tumor ascites harbors predominantly memory T cells. By examining the interaction between tumor ascites TAA-expressing PDC and tumor memory T cells, Aim 1 is to test our hypothesis that tumor PDC induce TAA-specific suppressive memory CD8+ T cell immunity. Lymph nodes (LNs) are the central priming sites for DC to initiate T cell immunity. LNs harbor predominantly naive T cells. Draining tumor LN-PDC co-localized with naive T cells. By examining the interaction between TAA expressing LN-PDC and LN naive T cells, Aim 2 is to test our hypothesis that draining tumor LNPDC induce TAA-specific suppressive naive CD8+ T cell immunity. B7-H1 is a member of the B7 T cell costimulatory family that induces T cell IL-10 and mediates tolerance/anergy. Tumor PDC highly express B7-H1 whose regulation and functional significance is unknown. Aim 3 is to test our hypothesis that tumor PDC B7-HI contributes to induce TAA-specific suppressive CD8+ T cell immunity.