Immunosuppressed Microenvironment – An Emerging Target in Prostate Cancer Management

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

Abstract:

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.

Keywords: Castrate-resistant prostate cancer, immunosuppression, ipilimumab, tumour microenvironment, myeloid-derived suppressor cells, S100A9, tumour-associated macrophages, radium-223, sipuleucel T, tasquinimod
Disclosure: Joaquim Bellmunt has participated in Advisory Boards for Ipsen, Dendreon and BMS related to the topic under discussion. Karim Fizazi has participated in Advisory Boards or been a speaker for Amgen, Sanofi, Janssen, Astellas, BMS, Novartis, Bayer, Orion and Dendreon. Geetha Srikrishna has no conflicts of interest to declare.
Acknowledgments: Geetha Srikrishna gratefully acknowledges financial support from the National Institutes of Health grant R21-CA127780 and Sanford-Burnham Institute Cancer Center/National Cancer Institute P30 grant CA030199-30. The authors would like to thank Dmitry I Gabrilovich for his valuable advice on this manuscript. Editorial Assistance was provided by Katrina Mountfort at Touch Medical Media.
Received: May 16, 2014 Accepted May 27, 2014 Citation European Oncology & Haematology, 2014;10(1):51–7
Correspondence: Geetha Srikrishna, Sanford-Burnham Medical Research Institute, 10901 North Torry Pines Road, La Jolla, CA 92037, US. E: gskhandrika@gmail.com
Support: The publication of this article was supported by Ipsen. The views and opinions expressed are those of the authors and do not necessarily reflect those of Ipsen.

Prostate cancer is the most common malignancy in males in the US and Europe: approximately 15.3 % of men will be diagnosed with prostate cancer at some point during their lifetime.1 The majority of patients are diagnosed at an early stage, at which treatments such as radiotherapy or surgery may be curative.2 The first-line treatment for metastatic or advanced prostate cancer is androgen deprivation therapy, which is effective initially, but relapse typically occurs after 18–24 months.3 Progression occurs via androgen receptor signalling, leading to the state of castrate-resistant prostate cancer (CRPC), for which the prognosis is poor.4,5 Current approved therapeutic options for advanced and CRPC include chemotherapy (docetaxel, cabazitaxel), immunotherapy (sipuleucel-T), bone targeted agents (denosumab, radium-223 [RA-223]) and new-generation endocrine therapies (abiraterone acetate, enzalatumide).

Despite major recent advances, metastatic CRPC (mCRPC) remains an incurable disease, although median survival times of up to 33 months have been reported in recent clinical trials6 compared with 1 year of median survival before the 2000s.7 Cross-resistance between hormonal agents has further complicated treatment approaches.8–10 Tumour immunosuppression is a well-established mechanism for the regulation of tumour growth. However, many immunotherapeutic strategies, despite their theoretical promise, have failed to bring about effective, consistent and durable responses in clinical trials of mCRPC. So far, sipuleucel T is the only immunotherapy that was shown to improve overall survival (OS) in mCRPC, though without improvement in progression-free survival (PFS) or quality of life (QoL).11 mCRPC therefore represents a substantial unmet clinical need. A better understanding of the microenvironment of prostate cancer may provide new treatment paradigms.

The microenvironment of a tumour is an essential part of its physiology as it provides a nurturing environment for the malignant process. It was previously thought that cancer cells had the potential to metastasise by releasing factors that modify normal cells into cancer cells. However, according to Paget’s 1889 ‘seed and soil’ hypothesis, ‘bad seed’ (tumours) will only grow in a ‘good soil’ (the tumour microenvironment). This hypothesis has been revisited flowing enhanced understanding of the tumour microenvironment: the mutual interaction between the tumour and its specific microenvironment contributes to tumour formation and metastasis.12Tumour cells often promote the development of an immunosuppressive microenvironment, which favours tumour growth and progression. A greater understanding of the mechanisms by which the immunosuppressed microenvironment interacts with tumour cells may lead to improved diagnostic and therapeutic approaches. This article aims to review our current understanding of the immunosuppressed tumour environment in prostate cancer and its therapeutic targeting.

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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