Abstract
BackgroundThe importance of B7-H molecules for the T cell/tumor communication and its impact on renal cell carcinoma (RCC) progression and prognosis has been recently described. Cytokine treatment of RCC has earlier been shown to be beneficial in preclinical settings, but its clinical implementation has not proven to be as effective. This might be partially explained by the yet incomplete picture of cellular alterations in tumor cells upon cytokine treatment investigated in detail in this study.MethodsRCC tumor cell lines were treated with different cytokines alone or in combination. The constitutive and/or cytokine-induced expression of cytokine receptors signaling components and B7-H molecules in RCC cells were analysed by qPCR and flow cytometry. A mcherry reporter gene construct containing B7-H1 promoter was cloned and its activity was determined upon transfection in cytokine-stimulated cells. Cytokine pretreated tumor cells were co-cultured with allogeneic CD8+ T cells from healthy donors and T cell proliferation as well as cytokine secretion was determined.ResultsA heterogeneous, but constitutive B7-H1,-H2,-H3 and H4 expression was found on human RCC cell lines. IL-4 and TNFα treatment led to strong synergistic induction of B7-H1 in RCC cells, whereas B7-H2 was only increased by TNFα. In contrast, B7-H3 and B7-H4 expression were not altered by these cytokines. Treatment of RCC cells with TNFα and IL-4 was accompanied by an activation of signaling molecules like NF-κB, IκB and STAT6. The cytokine-mediated up-regulation of B7-H1 was due to transcriptional control as determined by an increased B7-H1 promoter activity in the presence of IL-4 and TNFα. Despite HLA class I and LFA-1 were also increased, the cytokine-mediated up-regulation of B7-H1 was more pronounced and caused an inhibition of allospecifc CD8+ T cell proliferation.ConclusionThus, IL-4 and TNFα, which could be released by immune cells of the tumor microenvironment, are able to control the B7-H1 expression in RCC thereby altering T cell responses. These data are of importance for understanding the complex interplay of tumor cells with immune cells orchestrated by a number of different soluble and membrane bound mediators and for the implementation of check point antibodies directed against B7-H1.
Highlights
The importance of B7-H molecules for the T cell/tumor communication and its impact on renal cell carcinoma (RCC) progression and prognosis has been recently described
Using conventional qPCR TNFα, but not IL-4 mRNA expression levels were detected in the different RCC cell lines (Figure 1A)
Most of the RCC cell lines tested in the present study showed a very good and reliable response to IL-4 and TNFα treatment as demonstrated by phosphorylation of STAT6, enhancement of pNFκB and downregulation of IkB
Summary
The importance of B7-H molecules for the T cell/tumor communication and its impact on renal cell carcinoma (RCC) progression and prognosis has been recently described. Renal cell carcinoma (RCC) is the most common kidney cancer type with an incidence of 5.8 in 100.000 people in the Western world [1] causing death of 5327 patients/ year in Germany [2] These results document the need for ongoing research to identify novel therapeutic strategies and to investigate mechanisms of tumor immune escape. B7 family members are mainly described to modulate T cell responses as second signal in cooperation with the first signal, the antigen recognition mediated by binding of the T cell receptor (TCR) with the major histocompatibility complex (MHC). These signals can be of co-inhibitory or co-stimulatory nature. These antibodies are currently implemented in clinical trials demonstrating promising objective response rates in various tumors [8]
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