Interleukin-6 and vascular endothelial growth factor release by renal cell carcinoma cells impedes lymphocyte–dendritic cell cross-talk

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

“…ccRCC has been described as a proinflammatory neoplasia where tumor cells produce several cytokines (such as VEGF, IL6 and TGFb; refs. [33][34][35] that may lead to the recruitment and activation of polyclonal CD8 þ T cells (36)(37)(38)(39). Our data suggest that these recruited CD8 þ T cells could only be locally educated when high densities of TLS-DC are present, and in only in these cases their density correlates with favorable prognosis.…”

“…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

“…Interestingly, these two types of DCs display different phenotypes and capacities of T-cell priming, presumably due to the distinctive microenvironments in which they develop. Isolated DCs display an immature phenotype (CD80 À , CD86 À , CD83 À , and HLA-DR À ) (Gigante et al, 2009;Giraldo et al, 2015), express tumor-promoting molecules (eg, TNF-α and MMP-9) (Figel et al, 2011), and induce a dysfunctional in vitro T-cell activation (Cabillic et al, 2006;Figel et al, 2011). On the other hand, DCs within immune aggregates exhibit a mature phenotype and express activation markers Middel, Brauneck, Meyer, & Radzun, 2010;Troy et al, 1998) (Fig.…”

“…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).…”

Interleukin‐6 and its receptor in cancer

“…When tumor cells released low levels of IL-6, tumor antigen-expressing dendritic cells efficiently enhanced CTL activity. 142 Thus, IL-6 and VEGF release by RCC may inhibit host immune responses to the tumor.…”