Abstract
BackgroundRenal cell carcinoma (RCC) represents one of the most immunoresponsive cancers. Antigen-specific vaccination with dendritic cells (DCs) in patients with metastatic RCC has been shown to induce cytotoxic T-cell responses associated with objective clinical responses. Thus, clinical trials utilizing DCs for immunotherapy of advanced RCCs appear to be promising; however, detailed analyses concerning the distribution and function of DC subsets in RCCs are lacking.MethodsWe characterized the distribution of the different immature and mature myeloid DC subsets in RCC tumour tissue and the corresponding normal kidney tissues. In further analyses, the expression of various chemokines and chemokine receptors controlling the migration of DC subsets was investigated.ResultsThe highest numbers of immature CD1a+ DCs were found within RCC tumour tissue. In contrast, the accumulation of mature CD83+/DC-LAMP+ DCs were restricted to the invasive margin of the RCCs. The mature DCs formed clusters with proliferating T-cells. Furthermore, a close association was observed between MIP-3α-producing tumour cells and immature CCR6+ DC recruitment to the tumour bed. Conversely, MIP-3β and SLC expression was only detected at the tumour border, where CCR7-expressing T-cells and mature DCs formed clusters.ConclusionIncreased numbers of immature DCs were observed within the tumour tissue of RCCs, whereas mature DCs were found in increased numbers at the tumour margin. Our results strongly implicate that the distribution of DC subsets is controlled by local lymphoid chemokine expression. Thus, increased expression of MIP-3α favours recruitment of immature DCs to the tumour bed, whereas de novo local expression of SLC and MIP-3β induces accumulation of mature DCs at the tumour margin forming clusters with proliferating T-cells reflecting a local anti-tumour immune response.
Highlights
Renal cell carcinoma (RCC) represents one of the most immunoresponsive cancers
Immature dendritic cell (DC) are present within the tumour tissue To evaluate the total number of DCs in tumour tissues of RCCs and the corresponding normal kidney tissues, immunostaining for CD11c and Fascin was performed
Evaluation of immature and mature DC subsets was performed by immunhistochemistry for CD1a (Figure 1c) and CD83 (Figure 1d), respectively
Summary
Antigen-specific vaccination with dendritic cells (DCs) in patients with metastatic RCC has been shown to induce cytotoxic T-cell responses associated with objective clinical responses. Upon tissue damage or exposure to antigens, DCs capture antigens and subsequently migrate to the lymphoid organs, where they select the rare antigen-specific T cells and initiate a cellular immune response [1,2]. It has been shown that during migration and within secondary IL-12, which plays a critical role in the induction of efficient T-helper cell 1 immunity [10], as observed for an efficient anti-tumour T cell response [1,6]. The involvement of DCs in tumour immunity has clinical importance. The precise knowledge of the tumour environment, which varies between different tumour types, might be important for the design of optimal immunotherapeutic strategies against cancer [14,15,16]
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