Dendritic cells (DCs) essentially contribute to the induction and regulation of innate and adaptive immunity. Based on these important properties, DCs may profoundly influence tumor progression in patients. However, little is known about the role of distinct human DC subsets in primary tumors and their impact on clinical outcome. In the present study, we investigated the characteristics of human 6-sulfo LacNAc (slan) DCs in clear cell renal cell carcinoma (ccRCC). slanDCs have been shown to display various tumor-directed properties and to accumulate in tumor-draining lymph nodes from patients. When evaluating 263 ccRCC and 227 tumor-free tissue samples, we found increased frequencies of slanDCs in ccRCC tissues compared to tumor-free tissues. slanDCs were also detectable in the majority of 24 metastatic lymph nodes and 67 distant metastases from ccRCC patients. Remarkably, a higher density of slanDCs was significantly associated with a reduced progression-free, tumor-specific or overall survival of ccRCC patients. Tumor-infiltrating slanDCs displayed an immature phenotype expressing interleukin-10. ccRCC cells efficiently impaired slanDC-induced T-cell proliferation and programming as well as natural killer (NK) cell activation. In conclusion, these findings indicate that higher slanDC numbers in ccRCC tissues are associated with poor prognosis. The induction of a tolerogenic phenotype in slanDCs leading to an insufficient activation of innate and adaptive antitumor immunity may represent a novel immune escape mechanism of ccRCC. These observations may have implications for the design of therapeutic strategies that harness tumor-directed functional properties of DCs against ccRCC.
Chemotherapy is an important treatment modality for many patients with advanced cancer. Recent data revealed that certain chemotherapeutic agents differentially affect maturation, cytokine production and T-cell stimulatory capacity of dendritic cells (DCs), which play a crucial role in the induction of antitumor immunity. Whereas most reports are based on mouse or human monocyte-derived DCs, studies investigating the direct effect of chemotherapeutic drugs on native human DCs are rather limited. Here, we evaluated the impact of various chemotherapeutic drugs on the immunostimulatory properties of 6-sulfo LacNAc 1 (slan) DCs, representing a major subpopulation of human blood DCs. Because of their various antitumor effects, slanDCs may essentially contribute to the immune defense against tumors. We demonstrated that doxorubicin and vinblastine significantly impair the release of tumor necrosis factor-a, interleukin (IL)-6 and IL-12 by slanDCs. Functional data revealed that both drugs inhibit slanDC-mediated proliferation of T lymphocytes and their capacity to differentiate naive CD4 1 T cells into proinflammatory T-helper type I cells. Furthermore, these agents markedly suppressed the ability of slanDCs to stimulate interferon-c secretion by natural killer (NK) cells. In contrast, paclitaxel, mitomycin C and methotrexate sustained the ability of slanDCs to produce proinflammatory cytokines and their potential to activate T-lymphocytes and NK cells. These results indicate that doxorubicin and vinblastine impair the ability of native human DCs to stimulate important immune effector cells, whereas methotrexate, mitomycin C and paclitaxel maintain their immunostimulatory properties. These novel findings may have implications for the design of treatment modalities for tumor patients combining immunotherapeutic strategies and chemotherapy.
6-sulfo LacNAc+ (slan) DCs, representing a myeloid human blood DC subset, produce various proinflammatory cytokines, display cytotoxic activity and efficiently stimulate natural killer (NK) cells and T lymphocytes. Recent studies demonstrated that slanDCs accumulate in metastatic tumor-draining lymph nodes from cancer patients, indicating that slanDCs may contribute to antitumor immunity. We constructed tissue microarrays from primary clear-cell renal cell carcinomas (ccRCC) and paired non-neoplastic renal tissues from 265 patients who underwent radical/partial nephrectomy in the Department of Urology, University Clinic, TU Dresden. The slanDCs were identified by immunohistochemistry using a DD2 antibody, developed in the Institute of Immunology, TU Dresden. Freshly prepared tumor-infiltrating cells from 10 specimens were used for phenotypic characterization by flow cytometry. The effects of slanDCs and T-lymphocytes isolated from freshly prepared peripheral blood mononuclear cells on ACHN, CAKI-1 and on two native ccRCC cell lines were assessed by flow-cytomtery, proliferation assays. The frequency of slanDCs in ccRCC and paired non-neoplastic renal tissues were correlated with the clinico-pathological characteristics of patients. SlanDCs were detectable in the majority of primary tumors (93.2%), metastatic lymph nodes (87.5%) and distant metastases (85.1%). A significantly (p<0.001) higher number of slanDCs were detected in primary ccRCC tissues (mean: 3.74 slanDC/mm2, range: 0-19.82 slanDC/mm2) compared to tumor-free tissues (mean: 1.19 slanDC/mm2, range: 0-9.9 slanDC/mm2). A higher density of slanDCs in ccRCC tissues was significantly correlated with a higher grading and stage of the primary tumor (p = 0.001 and p = 0.006 respectively), as well as with lymph node- or distant metastases (p = 0.039 and p<0.001, respectively). Remarkably, a higher density of slanDCs was significantly correlated with a reduced progression-free, tumor-specific or overall survival of ccRCC patients. Freshly prepared ccRCC-infiltrating slanDCs expressed HLA-DR and low densities of CD86, but CD40, CD80, CD83 and CCR7 could not be detected. Whereas the proinflammatory cytokines TNF-α and IL-12 were not found, a proportion of slanDCs showed expression of the anti-inflammatory cytokine IL-10. Further studies revealed that primary ccRCC cells efficiently impair the capacity of slanDCs to stimulate CD4+ and CD8+ T-cell proliferation and Th1 programming. In addition, ccRCC cells significantly inhibited slanDC-mediated NK cell activation. These findings indicate that higher slanDC numbers in ccRCC tissues are associated with poor prognosis. The induction of a tolerogenic phenotype in slanDCs leading to an insufficient activation of innate and adaptive antitumor immunity may represent a novel immune escape mechanism of ccRCC. Citation Format: Marieta I. Toma, Rebekka Wehner, Anja Kloß, Kati Erdmann, Susanne Fuessel, Barbara Seliger, Dorothee Brech, Elfriede Noessner, Knut Schaekel, Manfred Wirth, Gustavo Baretton, Marc Schmitz. Accumulation of tolerogenic human 6-sulfo LacNAc+ dendritic cells in renal cell carcinoma is associated with poor prognosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1278. doi:10.1158/1538-7445.AM2015-1278
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