Immunosuppressive effect of renal cell carcinoma on phenotype and function of dendritic cells

Abstract

Dendritic cells (DCs) play an important role in anti-renal cell carcinoma (RCC) immunity. The aim of the study was to investigate effect of mimic RCC microenvironment on phenotype and function of DCs. We isolated conditioned media (CM) from supernatants of culturing RCC cells and adjacent non-RCC cells in patients. CD14+ monocytes were obtained from healthy donors. The monocytes derived DCs were treated by RCC CM and non-RCC CM. Maturation markers CD80, CD83, CD86, and HLA-DR on DCs were analyzed using flow cytometry, while the levels of IL-10, TGF-β, and IL12p70 in supernatants were examined by ELISA. The DCs migration treated with RCC CM and non-RCC CM was investigated using transwell assay. The DCs treated and allogenic T cells were co-cultured for detecting T-cell proliferation and change of phenotype on the T cells. Our results indicated that RCC CM inhibited the up-regulation of CD80,CD83, CD86, and HLA-DR in response to LPS in treated DCs and increased IL-10 and TGF-β secretion but reduced IL12p70 production. Moreover, the migration ability of DCs treated with RCC CM was also inhibited, compared to DCs treated with adjacent non-RCC CM. In addition, T-cell proliferation was suppressed in co-culture assay with DCs treated with RCC CM; proportion CD25+Foxp3+ regulatory T cells were induced to increase. This study suggests that RCC CM can inhibit maturation of DCs and impair its function; moreover, DCs treated with RCC CM induce regulatory T cells increase, thus could contribute RCC escape from antitumor immunity.

Orchestration and Prognostic Significance of Immune Checkpoints in the Microenvironment of Primary and Metastatic Renal Cell Cancer

“…Accordingly, several studies have shown that the ccRCC microenvironment can induce a dysfunctional DC maturation, a downregulation of costimulatory molecules and tolerogenicity (34,41,42), whereas DC in the TLS are likely to be protected from these effects (43). Altogether, our results suggest that the particular proinflammatory milieu initiated by tumor cells induces the recruitment of CD8 þ T cells that-due to the low number of fully functional mature DC present in specialized Tcell-priming sites, or the presence of DC with suppressive phenotype-are not able to mount an effective antitumor immune response, but rather express exhaustion/inhibition molecules.…”

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

“…This evidence suggests that RCC microenvironment is enriched in molecules that hamper DC activity and maturation, since their phenotypic abnormalities are restricted to cells embedded in the tumor stroma and can be reversed when they are removed from the tumor. In addition, conditioned media from RCC primary cultures or cell lines can induce in vitro tolerogenic and dysfunctional DCs (HLA-DR dim , CD80 À /CD86 À , IL-10 + /TGF-β + ) Song, Shurin, Tourkova, Chatta, & Shurin, 2004;Teng et al, 2014) by mechanisms dependent on IL-6, IL-8, and VEGF (Cabillic et al, 2006;Figel et al, 2011).…”

Immune consequences of anti-angiogenic therapy in renal cell carcinoma

“…Interestingly, additional expansion of Tregs was observed in RCC patients in response to IL-2 treatment, which explains the weak efficacy of this therapeutic approach [ 36 ]. Treg induction in RCC can be a consequence of impaired DC activation [ 41 ] and it was shown that other CD4+ cell populations of kidney cancer patients tend to express a naïve/resting phenotype although they do respond to non-specific activation in vitro [ 42 ]. In RCC cases it was shown that circulatory Tregs can differ from their intra-tumoural counterparts, which had increased levels of HLA-DR, Fas, and GITR and simultaneously possessed higher suppressive properties [ 37 ].…”