Immunosuppressed microenvironment - an emerging target in prostate cancer Management

Although the prognosis of metastatic castrate-resistant prostate cancer (mCRPC) has dramatically changed in the last decade, with median survivals improving from about a year to almost 3 years, current hormonal and chemotherapeutic approaches ultimately result in resistance. An enhanced understanding of the microenvironment of prostate cancer may explain the mechanisms underlying this resistance and provide novel therapeutic targets. The tumour microenvironment promotes the growth and spread of prostate cancer through suppression of immune responses. Many cellular and molecular components of the immunosuppressed tumour microenvironment have been identified as potential targets for therapeutic intervention, including myeloid-derived suppressor cells (MDSCs), tumour-associated macrophages (TAMs), toll-like receptors (TLRs) and the pro-inflammatory protein S100A9. Several agents have demonstrated an ability to modulate the tumour cell microenvironment, including immunotherapies such as sipuleucel T and ipilimumab. In preclinical models, tasquinimod has been shown to bind to S100A9 and therefore has the potential to affect accumulation and function of MDSCs as well as enhancing anti-tumour immune responses. It is now in phase III development. The bone microenvironment also represents a valuable therapeutic target: in clinical studies, denosumab, a rank-L inhibitor, delays time to first skeletal event, despite showing no improvement in overall survival (OS). Radium-223, an alpha-emitter with high bone affinity, delays bone metastasis as well as significantly improving OS.