Kidney Cancer
Immune Self-tuning in Renal Cell Carcinoma
Antonia Busse1 and Ulrich Keilholz2
1. Post-doctoral Research Fellow, Ludwig Institute for Cancer Research; 2. Professor of Medicine, and Vice Chair, Department of Haematology, Oncology and Transfusion Medicine, University Hospital Benjamin Franklin, Free University Berlin
Abstract
Although renal cell carcinoma (RCC) is an immunogenic tumour, and although there is evidence that in a small proportion of cases antitumour immune responses may mediate tumour regression or at least disease stabilisation, patients with progressive disease have no effective antitumour immune response. Besides preventing recognition of the tumour by immune effector cells, RCC escapes the immune system by induction of tolerance through manipulating the function and proliferation of immune effector cells. This tuning of the immune response can occur by active suppression of immune effector cells through inhibitory molecules expressed on the tumour surface and through various tumour-secreted soluble factors, or it can be mediated indirectly by induction of immunosuppressive cells. This review provides an overview of the most common mechanisms that mediate immune tolerance in RCC and discusses the therapeutic perspectives of immunoregulatory strategies in the era of targeted therapies.
Keywords
Renal cell carcinoma (RCC), immune escape, T-cell dysfunction, regulatory T cells, myeloid-derived suppressor cells, vascular endothelial growth factor (VEGF), HLA-G, B7-H1, apoptosis-inducing ligands
Disclosure: The authors have no conflicts of interest to declare. Received: 28 September 2009 Accepted: 24 February 2010 Citation: European Oncology, 2010;6(1):70–5 Correspondence: Antonia Busse, Department of Medicine III, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany. E:
antonia.busse@charite.de
There is a large body of accumulated evidence that renal cell carcinoma (RCC) is an immunogenic tumour. Spontaneous and complete regressions of RCC metastases have been reported to occur, albeit in very rare cases.1,2
infiltration of RCC tumours by mononuclear cells,3,4
A few studies have reported profuse which may be
immune-mediated or caused by non-specific inflammatory responses. However, in some patients tumour-specific T-cell lines and clones have been expanded from tumours.5–7
Therefore, as RCC is almost completely refractory to conventional treatments such as chemotherapy and radiation, early therapeutic strategies concentrated on immunotherapy.1,2,8
Before the approval of
tyrosine kinase inhibitors (TKIs), cytokine therapy with interferon-α (IFN-α) and/or interleukin-2 (IL-2) was considered the standard treatment of metastatic RCC. However, durable and complete response rates were relatively rare, and clinical response rates reached no more than 20%.1,2,9–12
effectively mediating tumour regression and were more susceptible to cell death upon activation.16–19
On the molecular level, alterations in
the expression and activity of intracellular signalling elements have been reported in RCC patients, including a decreased expression of the T-cell receptor (TCR) ζ chain (CD3ζ) and reduced tyrosine kinase activity,20–22
nuclear factor kappa B (NFκB).23–25
frequently undermines spontaneous or immunotherapy-induced effector cell function.
Other immunotherapeutic strategies,
such as vaccination, resulted in promising immunological responses in patients with advanced RCC, but clinical efficacy remained low.13
A number of studies have shown that the cytokine profile observed both intratumorally and in the peripheral blood of patients with active disease is most consistent with a type 2 bias,5,14–16
infiltrating T cells within RCC tumours were paradoxically associated with diminished cancer-specific survival.3,4
The strategies RCC develops to evade antitumour immunity are frequent and quite diverse, suggesting the crucial importance of immune escape for tumour progression. Besides loss of tumour antigen expression, downregulation or even loss of molecules involved in antigen processing and/or presentation is a common immune escape mechanism in RCC leading to the failure of fully competent T cells to mount a productive immune response, a phenomenon also called T-cell ignorance26–28
(see Table 1). Moreover,
tumours can express anti-apoptotic molecules, leading to resistance to killing by T cells or natural killer (NK) cells.29
and high levels of T-cell infiltrates within
and surrounding tumour lesions were frequently composed of dysfunctional lymphocytes that had been rendered incapable of
70
Another strategy by which RCC escapes the immune system is the induction of tolerance by manipulating the function and proliferation of immune effector cells. This immunomodulation or tuning of the immune response can occur by a variety of mechanisms. In the following sections we will provide an overview of the most common mechanisms that mediate immune tolerance in RCC.
© T O UCH BRIEFINGS 2010
as well as defective activation of the transcription factor These data suggest that RCC
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