Oncology Renal Cell Carcinoma
Figure 2: Suggested Immunomodulatory Effects of Targeted Therapies Based on In Vitro and In Vivo Analyses
Sorafenib Sunitinib
application of cyclophosphamide, known to downregulate Treg frequency and activity, could not enhance clinical or immunological efficacy of an allogenic DC vaccine.107
MDSC Tc1 Sunitinib Th1 Treg Sorafenib
Sunitinib Sorafenib
RCC cell
Vascular endothelial growth factor (VEGF), which inhibits maturation/function of dendritic cells (DCs) and promotes generation of myeloid-derived suppressor cell (MDSCs), is bound by the anti-VEGF antibody bevacizumab. Sunitinib promotes the function of mature DCs (mDCs) and reduces the number of MDSCs. Moreover, sunitinib reduces the number of Tregs and leads to a shift to type 1 immune response – likely by an indirect mechanism (dotted line). Sorafenib inhibits the function of mDCs and proliferation of Treg as well as CD4+ and CD8+ T cells.
Induction of Immunosuppressive Cells In addition to these active mechanisms described above, RCC also indirectly mediates immunosuppression by inducing cells with immunosuppressive properties, specifically regulatory T cells and dysfunctional APCs, which suppress the host antitumour responses both locally at the tumour site and systemically.
Regulatory T Cells
Natural and inducible T regulatory (Treg) cells are subsets of T lymphocytes able to suppress immune responses by direct interaction with other immune cells or through cytokines like IL-10 or TGF-β. They are characterised by expression of CD4, high-level expression of CD25, expression of glucocorticoid-induced TNF receptor (GITR), cytotoxic lymphocyte antigen-4 (CTLA-4) and the forkhead box P3 transcription factor FOXP3.98
As in a variety of
other malignancies, increased frequencies of peritumoral or circulating Tregs have also been observed in RCC patients with either localised or advanced disease.99–102
They may be induced
from CD4+ CD25– T cells or expanded from pre-existing Tregs by cytokines such as IL-10 and TGF-β that are produced by the tumour or tumour-associated myelomonocytic cells.98
Both increased
peripheral circulating Tregs and peritumoral Tregs have been reported to be associated with worse prognosis in RCC.101–103 Moreover, a decrease in peripheral Treg cell frequencies may be correlated with clinical response to IL-2 immunotherapy;99,101 however, the effect of IL-2 on expansion and function of Tregs is controversially discussed.102,104,105
Several attempts have been undertaken to eliminate or to functionally inhibit Tregs to boost the efficacy of immunotherapy protocols.106 Danull et al. showed that elimination of Tregs by a diphtheria-toxin- labelled anti-IL-2-receptor antibody (IL-2 diphtheria toxin conjugate DAB389IL-2, denileukin diftitox, ONTAK) before vaccination with mRNA-transfected DC strongly enhanced induction of vaccine-reactive T-cell responses without inducing toxicity on other cellular subsets with intermediate or low expression of CD25.100
By contrast, 30
Moreover, MDSCs have been shown to inhibit the T-cell response by depletion of arginine, mainly due to secretion of arginase I, which leads to distinct molecular changes in T-cells: a decrease in the expression of T-cell CD3ζ chain and impairment of T-cell signal transduction; and the inhibition of the cell cycle in the G0 phase.113
In
In vitro depletion of MDSCs from the peripheral blood samples re-established T-cell proliferation and function.113,114 As high levels of VEGF have been shown to be associated with an increase in MDSCs in cancer patients,115,116
treatment with the
anti-VEGF antibody bevacizumab could lead to a decrease in MDSC frequency, as shown in various murine tumour models.79,117
However,
in contrast to the observation in mice, treatment of advanced RCC patients with bevacizumab did not reduce the accumulation of MDSC in peripheral blood.113
EUROPEAN UROLOGICAL REVIEW
RCC patients, increased numbers of MDSCs in the peripheral blood correlated with increased arginase activity in peripheral blood mononuclear cells (PBMCs), low L-arginine and high ornithine levels in plasma and a profound T-cell dysfunction and decrease in T-cell proliferation.112–114
mDC Bevacizumab
Tumour-associated Myelomonocytic Cells Growing tumours inhibit the immune system by directly interfering with the differentiation, function and activation of APCs, such as DCs, monocytes or macrophages.108,109
VEGF
Tumour-associated macrophages
(TAMs), which represent the major inflammatory component of the stroma of many tumours, are characterised by the M2 phenotype and favour tumour progression not only by promoting tumour cell proliferation, angiogenesis, matrix remodelling and tumour migration, but also by suppression of adaptive immunity.108
Tumour-derived
factors have been shown to induce the expression of TGF-β as well as IL-10, PGE2 and TNF-α,110
of cell-surface molecules involved in antigen presentation as well as their endocytic capacity.69
Moreover, by secretion of VEGF, GM-CSF, TGF-β, IL-10, IL-6 or PGE2, RCC arrests differentiation of APCs from its myeloid progenitors and triggers accumulation of myeloid-derived suppressor cells (MDSCs), a heterogeneous population of monocytes/macrophages, granulocytes and DCs at different stages of differentiation.109,111
which downregulate the expression
They are negative
for CD14, CD80, CD86 and major histocompatibility complex class II (MHCII) and express high levels of VEGFR164,111,112
and CD11b as a
common marker, but may vary in their maturation markers, depending on the combination of factors produced by the tumour. As TAMs they promote angiogenesis and the development of Tregs, and their accumulation is associated with progressive tumour growth.108,109 They are suggested to engage an active cross-talk with TAMs to promote a generalised skewing of CD4 and CD8 T-cell immunity towards a type 2 response.
MDSCs isolated from RCC patients, but not from healthy donors, were capable of suppressing antigen-specific T-cell responses in vitro through the secretion of reactive oxygen species and nitric oxide upon interaction with cytotoxic T lymphocytes (CTL), which was reversible in vitro by exposing cells to the reactive oxygen species inhibitors. All-trans-retinoic acid (ATRA) was capable of abrogating MDSC-mediated immunosuppression and improving T-cell function by direct differentiation into APC precursors.111
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