Immunosuppressed Microenvironment – An Emerging Target in Prostate Cancer Management

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

The Role of the Tumour Microenvironment in Prostate Cancer Development, Progression and Control
In order for a tumour to progress and develop into a life-threatening entity, it must develop certain attributes. These include the ability to move, to degrade tissue matrix, to survive in blood and to being able to establish itself in a new tissue environment. It obtains these attributes via signals from the microenvironment that turn on gene transcription.13 The transformation of proliferating stem cells and subsequent tumour invasion depends on complex interactions between cancer cells and a microenvironment of activated inflammatory cells and stromal cell elements.14 In addition to these components, the tumour microenvironment includes matrix-degrading enzymes, endothelial cells and fibroblasts15 as well as factors that stimulate angiogenesis.16 Fibroblasts are able to buffer the acidity generated in the hypoxic conditions of the microenvironment, allowing more cells to survive the low pH, therefore increasing tumour progression.17

At distal metastatic sites, immune cells and fibroblasts establish premetastatic niches, providing permissive environments for migrating tumour cells to colonise and establish metastasis. Primary and metastatic sites communicate through soluble mediators and exosomes both from primary tumour cells and from immune and stromal cells of the tumour microenvironment.18 In addition, a number of secreted proteins derived from the tumour microenvironment have been found to attenuate the effects of cytotoxic chemotherapy in vivo, promoting subsequent treatment resistance.19,20

In prostate cancer, the unexpected finding that earlier-stage prostate cancer may be more resistant to chemotherapy than CRPC21 has led to the suggestion that prostate cancer passes through a microenvironment dependent state and progresses to a microenvironment-independent state.22 Since chemotherapy predominantly affects tumour cells, this finding suggests that targeting tumour cells is insufficient to prevent prostate cancer progression and that prostate cancer therapies should target the tumour microenvironment. Unlike tumour cells, stromal cells within the tumour microenvironment are genetically stable and therefore represent an attractive therapeutic target with reduced risk of resistance and tumour recurrence.18 Chronic inflammation of the prostate also plays a major role in the development of prostate cancer. Epidemiological studies show that prostate cancer is more common in populations with higher levels of baseline inflammation.23 Inflammatory cytokines promote sustained activation of the transcription factor nuclear factor kappa B (NF-kB), which is correlated with metastatic progression to CRPC.24

Immunosuppressive Components of the Tumour Microenvironment
Inflammation leads to disruption of the immune response and regulation of the tumour microenvironment, although the mechanisms by which specific inflammatory mediators contribute to tumour progression are not fully understood.24 Therefore, recent research has focused on modulation of the immune components of the tumour microenvironment.

As tumours progress, a number of mechanisms are activated that enable them to evade immune surveillance.25,26 Myeloid cells, a heterogeneous population of cells derived from the bone marrow, are actively recruited to the tumour microenvironment.26 Two types of myeloid cells: myeloidderived suppressor cells (MDSCs) and tumour-associated macrophages (TAMs) have been the focus of particular attention.26–29 The levels of MDSCs are greatly enhanced in humans during chronic pathological conditions such as infections, inflammation and cancer. MDSCs are immature myeloid cells that fail to complete their differentiation under chronic conditions typically encountered in the tumour microenvironment and lack the expression of mature myeloid cell surface makers.30 MDSCs inhibit innate and adaptive immunity, promoting tumour immune escape. This is achieved by numerous mechanisms including secretion of cytokines and upregulation of nitric oxide, production of reactive oxygen species (ROS), activation of L-arginase and sequestration of cystine, leading to T cell apoptosis, the nitration of chemokines and T cell receptors, blocking T cell migration and tumour cell killing and ultimately resulting in the inhibition of cytokine production that are crucial for T cell anti-tumour functions.27,29,31–34 MDSCs also impair immune cell function in the tumour microenvironment, an important step in tumour progression. MDSCs inhibit the activation of cells with cytotoxic anti-tumour activity and regulatory natural killer (NK)/NK T (NKT) cells,35,36 as well as modulating the de novo development of regulatory T cells (Tregs) 36

In addition to their immunosuppressive role, MDSCs can also directly stimulate tumour growth and expansion by stimulating pro-angiogenic cytokines and creating a favourable environment for metastasis (see Figure 1).29,30,37 MDSCs are actively recruited to the tumour microenvironment from the bloodstream, a process mediated by chemokines, integrins and adhesion factor molecules, which allows further accumulation of these cells in the tumour microenvironment.28 Hypoxia also stimulates the recruitment of circulating myeloid cells to tissues by promoting expression of genes associated with angiogenesis, metastasis and invasion, which is controlled by transcription factor complexes of hypoxia-inducible factors (HIFs).38

Levels of circulating MDSCs increase with age and are elevated in individuals in remission from cancer. This may be a result of age-related increased levels of inflammatory cytokines that facilitate the formation of MDSCs. Individuals in remission from cancer may continuously produce factors that promote the development of MDSCs.35 This raises a number of questions: do individuals with high levels of MDSCs have a microenvironment that supports tumour growth, and hence have increased risk of developing cancer? Do patients with a history of cancer undergo permanent changes in MDSC production? If so, could this contribute to an increased risk of developing seemingly unrelated cancers or other chronic inflammatory conditions? Larger studies are required to further explore these hypotheses.

The second important cellular components of the tumour microenvironment are TAMs, which have numerous roles in cancer progression (see Figure 2).28,39 In tumour microenvironments, TAMs are polarised towards the M2 phenotype, which affect diverse processes such as suppression of adaptive immunity, promoting angiogenesis, tumour cell proliferation and metastasis during tumour progression.40,41 By contrast, the ‘classically activated’ M1 phenotype promotes immune responses and inhibits angiogenesis, thus suppressing tumour development. The M2 TAMs secrete growth factors and cytokines, causing matrix remodelling, and suppression of the immune system’s ability to alert other immune cells to the presence of cancer cells.42 High levels of TAMs have been associated with poor prognosis in prostate cancer.43 MDSCs and TAMs therefore represent a promising target for therapeutic intervention. Strategies may include inhibition of recruitment to the tumour microenvironment, which may reduce resistance to chemotherapy,44 or partial reprogramming of TAM polarisation towards an M1-like phenotype.

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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