Abstract 1278: Accumulation of tolerogenic human 6-sulfo LacNAc+ dendritic cells in renal cell carcinoma is associated with poor prognosis

Abstract

Abstract 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