Oncology Renal Cell Carcinoma


Table 1: Immune Escape Mechanisms Involving Antigen Processing and Presentation in Renal Cell Carcinoma Affected Molecules


Molecular Mechanisms HLA class I molecules Direct mechanism: total or partial loss/downregulation of HLA class I APM molecules: • immunoproteasome subunits LMP2 and LMP7


• transporter-associated proteins: TAP1/TAP2 • tapasin


Co-stimulatory molecules: B7-1/B7-2


Lack of expression of co-stimulatory molecules APM = antigen-processing machinery; HLA = human leukocyte antigen. 138, 139


molecules or loss of heterozygosity due to mutations, transcriptional/ post-transcriptional regulation Indirect mechanism: downregulation of other APM components Reduced or lack of expression of APM components mainly due to dysregulation at the transcriptional or post-transcriptional level


References 129–133


26, 27, 133–137


Active Suppression of Immune Effector Cells by Inhibitory Molecules Expressed by the Tumour


Co-stimulatory Molecules Inhibiting T-cell Responses RCC cells constitutively express immunosuppressive co-stimulatory glycoproteins of the B7 family on their cell surface at a high frequency.30


The best analysed molecule is B7-H1 (programmed death


The interaction of B7-H1 with its receptor PD1 on T cells is able to induce apoptosis in activated T cells or to impair cytokine production and cytotoxicity of activated antitumour T cells.31–33


ligand 1, PD-L1).30,31


In vivo monoclonal antibody-mediated blockade of B7-H1 has been shown to potentiate antitumour responses and to promote in vivo tumour regression in several murine cancer models.31,33–35


In


RCC, aberrant B7-H1 expression was found not only in primary and metastatic tumour tissue but also on tumour-infiltrating mononuclear cells,36


predictor of prognosis.37,38


and correlated with aggressive pathological features,36 increased disease progression, cancer-specific death and overall mortality.37


trogocytosis, and cells that have acquired membrane-bound HLA-G1 by this mechanism act as regulatory cells – although for a limited amount of time. However, HLA-G may also have a long-term inhibitory function through HLA-G+ regulatory cells.44


In comparison with other


HLA-G is induced by stress, hypoxia, IL-10, glucocorticoids, IFN, granulocyte–macrophage colony-stimulating factor (GM-CSF), gangliosides and the leukaemic inhibitory factor.43 Additionally, epigenetic mechanisms have been shown to play an important role in HLA-G regulation.50,51


Apoptosis-associated Ligands


Therefore, B7-H1 is suggested as an independent According to these results, PD1 expression


on tumour-infiltrating lymphocytes (TILs) was associated with poor outcome in RCC patients.39


Furthermore, expression of B7-H4 (B7x,


B7S1) or B7-H3 in RCC tissue was associated with adverse clinical and pathological features and was found to be an independent risk factor for RCC-associated death.40,41


Interestingly, in contrast to


B7-H1, B7-H4 and B7-H3 are preferentially expressed in the tumour vascular endothelium. Moreover, elevated B7-H4 serum levels could be detected in RCC patients, correlating with advanced tumour stage.42


Although the receptor for B7-H4 has yet to be identified,


in vitro studies suggested that B7-H4 may deliver an inhibitory signal to T cells, thereby abrogating CD4+ and CD8+ T-cell proliferation, cell-cycle progression and IL-2 production.2–4


Human Leukocyte Antigen-G


In contrast to classic human leukocyte antigen (HLA) class I antigens, HLA-G is characterised by a limited polymorphism and a physiological expression mainly restricted to the placenta, thymus, pancreatic islets, erythroid and endothelial cell precursors and immune-privileged tissues such as the eye and testes.43,44


There are at least seven


alternatively spliced messenger RNA (mRNA) transcripts that encode for membrane-bound HLA-G (HLA-G1–4) and soluble HLA-G (HLA- G5–7).44


By binding inhibitory receptors such as immunoglobulin-like transcript 2 (ILT2), ILT4 and killer-cell immunoglobulin-like receptor two domains long cytoplasmic tail 4 (KIR2DL4), HLA-G prevents lysis by NK cells and T cells and promotes a T-helper cell type 2 (Th2) response.44,45


Moreover, HLA-G can transfer from cell to cell by 28


Destruction of immune effector cells, by either directly inducing T-cell apoptosis or sensitising T-lymphocytes to activation-induced cell death, represents one potential mechanism to account for the observed defects in the clonal expansion and cytotoxic function of RCC-reactive T cells.17,52,53


however, only a few genes, such as


tumour entities, the expression of HLA-G is relatively high in RCC. On the mRNA and protein level it was found in 45–60% of cases, independent of grading and stage of tumour, but its expression was subtype-specific, as it was mainly found in clear cell RCC but not in papillary RCC.46–49


Gene expression studies have shown an


upregulation of several immune-regulatory molecules that are capable of inducing apoptosis;54


FasL and CD70, have been shown to be relevant for RCC immune escape.17,55


Overexpression of CD70 promotes lymphocyte apoptosis through its interaction with its CD27 receptor and the intracellular receptor-binding protein SIVA.55


Overexpression of FasL has been confirmed in many studies. Uzzo et al. were the first group to provide functional evidence17


for


tumour-induced apoptosis of T cells via the expression of FasL. In concordance, increased Fas R expression was found in TILs of RCC.17,56 Moreover, FasL expression has been reported to be negatively correlated with prognosis in various cancers, and in some, but not all, studies of RCC.57–60


Active Suppression of Immune Effector Cells by Soluble Factors


Cytokines and Growth Factors


RCC is known to produce various cytokines, such as tumour necrosis factor-alpha (TNF-α), transforming growth factor beta (TGF-β), IL-1β, IL-6 and IL-10, and growth factors, such as vascular endothelial growth factor (VEGF) or GM-CSF,15,18,62,63


that promote not EUROPEAN UROLOGICAL REVIEW


It has been shown that soluble products derived from RCC inhibit the proliferative capacity of T cells infiltrating human tumours, due to a downregulation of Janus kinase 3 (Jak 3), p56 (Lck), p59 (Fyn) and Zap 70.20,22,61


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