Immunosuppressed Microenvironment – An Emerging Target in Prostate Cancer Management

European Oncology & Haematology, 2014;10(1):51–7

The Role of Secreted and Receptor Proteins in the Immunosuppressed Tumour Microenvironment
In addition to cellular components, other immune components of the tumour microenvironment, including chemokines and cytokines, contribute to tumour growth, progression and host immunosuppression.36,45 Interactions of cancer cells with both cellular and non-cellular components of this microenvironment are mediated via secreted and receptor proteins and specialised proteins that bind to matrix collagen, providing signals for cancer growth and metastasis. Pattern recognition receptors such the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4) expressed on tumour cells and myeloid cells in the tumour microenvironment interact with damage-associated molecular pattern (DAMP) molecules in the tumour microenvironment. This interaction leads to sustained activation of intracellular signalling pathways, promoting tumour progression.

RAGE is a membrane-bound or soluble protein that is markedly upregulated by stress and inflammatory mediators in epithelial and myeloid cells, and persistent activation of the receptor underlies many chronic diseases.46 The TLR4 is involved in many chronic inflammatory conditions and also has a major role in signalling in the tumour microenvironment. Its activation by immune cells leads to increased tumour-promoting factors, including nitric oxide synthase (NOS2) and cyclooxygenase-2 (COX2), as well the recruitment of immunosuppressive cell types that reduce host tumour surveillance and diminish therapeutic response.47 TLRs recognise DAMPs, which are nuclear or cytosolic proteins released during cell necrosis. DAMP activation of TLRs initiates signalling cascades, resulting in the release of chemokines and cytokines, pro-angiogenic factors and growth factors, which promote tumour progression. Enhanced TLR expression within the tumour microenvironments has made these molecules attractive therapeutic targets. The role of TLR4 in prostate cancer has not yet been fully established, and further studies are warranted.48

Among the ligands for RAGE and TLR4, DAMP molecules S100A8/A9 and Ca2+-binding proteins with well-known roles in inflammation, have increasingly been recognised as having major roles in tumour growth and metastasis (see Figure 3).49 While S100A8/A9 proteins are powerful apoptotic agents and, in high levels, exhibit anti-tumour properties in vitro, the expression of lower levels in cancer cells has been associated with tumour development, cancer invasion or metastasis.50 They are downregulated during normal differentiation of myeloid precursors in the bone marrow to dendritic cells and macrophages. However, tumourderived factors initiate the upregulation of S100A9. This promotes the generation of MDSCs.49,51 MDSCs express carboxylated glycans, which provide binding sites for S100A8/A9, promoting activation of intracellular signalling pathways and supporting an autocrine feedback that causes further accumulation of MDSCs, which then migrate to tumours.52 S100A8/A9 produced in the tumour microenvironment also interacts with RAGE on tumour cells and promote downstream signalling and expression of protumourigenic genes that lead to subsequent tumour progression.53

In addition to their role in MDSC generation, S100A8/A9 mediate the inflammatory and migratory potential of myeloid cells.54 S100A8/A9 have pro-inflammatory actions, and activate mitogen-activated protein kinase (MAPK) signalling pathways and NF-kB,49,55 partly mediated by their interaction with RAGE.56 S100A8/A9 proteins play an important role in metastasis, contributing to the establishment of a pre-metastatic niche comprising immature myeloid cells, MDSCs and endothelial cells, providing a microenvironment that supports the adhesion and invasion of disseminated tumour cells.49,54,55,57 They also recruit inflammatory and tumour cells to metastatic sites.54,58–60

S100A9 is strongly expressed in human prostate cancer epithelial cells,61 and high levels of S100A8/A9 have been associated with time to prostate cancer recurrence.62 Their expression in prostate cancer cell lines is increased by hypoxia and HIF-1.62 Furthermore, the presence of circulating S100A9 has been proposed as a diagnostic marker to distinguish prostate cancer from benign prostate hyperplasia.61

A recent study showed that S100A8/A9 expression in epithelial prostate cancer cells causes enhanced infiltration of immune cells, especially neutrophils, and stimulates settlement of the cancer cells in the lung.63

Both RAGE and TLR4 have been implicated in S100A8/A9 mediated effects in tumour progression. S100A9-TLR4 interaction promotes prostate tumour growth.64 Other RAGE ligands have also been implicated in prostate tumour growth.65 Which receptor is predominant depends on the tumour type, the cell types involved and glycation modifications on the receptor.49 Therefore, inhibiting the function of S100A8/A9 by small molecule inhibitors may provide a novel therapeutic approach to prostate cancer.

Therapeutic Agents Targeting Components of the Tumour Microenvironment
There has been increasing interest in novel therapies that interact with the tumour microenvironment rather than the tumour itself. A number of cancer therapies that target the tumour microenvironment are in current clinical use in other solid tumours. These include the monoclonal antibodies trastuzumab for breast and gastric cancers and rituximab for haematological malignancies; bevacizumab, sunitinib and sorafenib; and agents that inhibit osteoclast function (the bisphosphonate zoledronate and the RANKL inhibitor denosumab).66

Several microenvironment strategies are in clinical development for prostate cancer and include anti-angiogenesis, integrin signalling and immune pathways. Since prostate cancer is typically a slow-progressing disease, the use of immunotherapy is particularly advantageous in terms of targeting advanced tumours and inducing anti-tumour immunity. Immunotherapies in clinical development include vaccines and antibody-based immunotherapies targeting checkpoint inhibitors.67 Sipuleucel-T is an autologous cellular vaccine consisting of activated antigen-presenting cells loaded with prostatic acid phosphatase. In the pivotal Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) phase III study, men treated with sipuleucel-T (n=341) had a median OS of 25.8 months compared with the placebo group (n=171), who had a median OS of 21.7 months, a relative reduction of 22 % in the risk of death compared with the placebo group (hazard ratio [HR] 0.78; 95 % confidence interval [CI] 0.61 to 0.98; p=0.03). However, no difference in PFS was noted. Adverse events (AEs) were more frequently reported in the sipuleucel-T group than in the placebo group, including chills, fever and headache.11 Based on these results, in 2010 sipuleucel-T received approval from the US Food and Drug Administration (FDA), the first therapeutic vaccine approved for any type of cancer in the US.

Ipilimumab is a fully human, monoclonal antibody (mAb) against cytotoxic T lymphocyte antigen 4 (CTLA-4), which regulates T cell responses and downregulates the immune response to tumour cells.68 Two phase III trials in the first- and second-line treatment of mCRPC have recently completed accrual.69,70 Results of one of these studies were recently reported. Men were randomised to bone-directed radiotherapy before either ipilimumab (n=399) or placebo (n=400).70 Median OS with ipilimumab was not significantly improved compared with that with placebo (11.2 versus 10 months, HR=0.85, 95 % CI 0.72–1.00; p=0.053). Treatment-related AEs were common and mainly immune-related. Patients without visceral metastases seemed to benefit more, emphasising the importance of optimal patient selection in trials evaluating vaccines and other immunotherapeutic agents for CRPC.

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Keywords: Castrate-resistant prostate cancer, immunosuppression, ipilimumab, tumour microenvironment, myeloid-derived suppressor cells, S100A9, tumour-associated macrophages, radium-223, sipuleucel T, tasquinimod