Immune Driver of Castration-Resistant Prostate Cancer Identified

A novel mechanistic insight on how prostate cancer can become insensitive to androgen deprivation and androgen receptor blockade

New understanding of a mechanism of the disease progression that characterises castration-resistant prostate cancer (CRPC) following successful standard of care (SoC) treatment with chemical enabled androgen deprivation therapy may provide novel approaches to prevent the more than 300,000 deaths worldwide that are annually attributed to this disease. 

Using human biopsy samples and mouse models of prostate cancer, a team led by Andrea Alimonti of the Institute of Oncology Research, Oncology Institute of Southern Switzerland in Bellinzona, Switzerland described how a secretion of myeloid cells in the patient’s immune system may drive treatment resistance in an article published in the journal Nature. 

Over 70 years ago, the link was established between the growth of prostate cancer and androgen hormones that are produced in the testes. This discovery led to the SoC therapy of androgen deprivation therapy (ADT) by chemicals broadly referred to as luteinizing hormone-releasing hormone (LHRH) agonists. However, disease progression, or CRPC, eventually occurs despite low androgen levels.  

Higher levels of MDSCs in the tumour microenvironment found in patients with CRPC 

Several mechanisms that contribute to CRPC have been proffered, and some or all may work together in the development of resistence. Therefore, drugs have been designed to inhibit androgen biosynthesis and this therapy results in tumour shrinkage. However, resistence to these agents may also develop, leading to a need to elucidate additional mechanisms and new drug development. 

By comparing tumour biopsy samples of patients with CRPC to samples of patients with prostate cancer but no resistance development, Prof. Alimonti and colleagues found that immune cells known as myeloid-derived suppressor cells (MDSCs), may drive CRPC. 

MDSCs include monocytes and neutrophils that are in an immature state of abnormal activation. Previous reports have linked the presence of MDSC to a poorer prognosis. The investigators noted that, indeed, the tumour biopsies in patients with CRPC did have more MDSCs expressing CD11b, CD33, and CD15 than patients with prostate cancer that had not progressed to the castration-resistant stage. 

In murine models, the investigators determined that surgical castration resulted in increased recruitment of MDSCs to tumours, compared with mock castration done in control animals showing little recruitment of MDSCs. 

The team grew mouse MDSCs in vitro and isolated the culture medium. They then demonstrated that the proliferation and growth of androgen-dependent prostate-cancer cell lines cultured in vitro under androgen deprivation could be stimulated by adding this medium. Furthermore, adding the medium also stimulated an increase in the transcription of genes with expression that is normally under the control of the androgen receptor. 

Similar experiments using human cells confirmed these findings. Conversely, the investigators found that pharmacological techniques to deplete MDSCs could delay the development of castration resistance in mice. 

CRPC may be driven by secretion of IL-23 by the myeloid cells of the patient 

By comparing the levels of gene expression in surgically- versus mock-castrated mice, the investigators identified upregulation of the gene coding for the IL-23 cytokine and another gene encoding a subunit of the receptor to which IL-23 binds. Using the prostate-cancer specimens, they were able to confirm that there were more IL-23-expressing MDSCs in CRPC specimens than in specimens from tumours that were not castration resistant. 

The team also found that blocking IL-23-mediated signalling in mice postponed the development of CRPC. 

The investigators turned to exploring the signalling pathway downstream of IL-23 that promotes renewed tumour growth by investigating the IL-23-regulated proteins STAT3 and RORγ, which stimulate signalling via the androgen-receptor signalling. This study was based on a model wherein IL-23-mediated activation of the STAT3–RORγ pathway led to increased expression of the androgen receptor and increased expression of genes controlled by the androgen receptor. In mouse models of CRPC, the team found that blockage of IL-23 by antibody and inhibiting androgen receptor signalling with enzalutamide was able to reverse castration resistance and resulted in tumour shrinkage. 

Conclusions 

The investigators concluded that IL-23 secreted by MDSCs and by the IL-23 receptor on prostate cancer cells promotes the development of CRPC. 

These data offer a novel mechanistic insight on how prostate cancers can become insensitive to androgen deprivation and androgen receptor blockade. The findings further suggest the development of new pharmacological or genetic approaches to treat CRPC. 

The authors pointed out that anti-IL-23 antibodies have been shown to be well-tolerated in clinical trials involving patients with auto-immune diseases and suggest that anti-IL-23 should be clinically evaluated in men with resistant prostate cancer. They proposed an immunotherapeutic strategy targeting paracrine IL-23 with antibodies in combination with established endocrine anticancer treatments such as enzalutamide would be likely to improve outcomes for men with CRPC. 

These findings and the proposed novel treatment warrant further evaluation in clinical trials. 

Disclosure 

No external funding was disclosed. 

Reference 

Calcinotto C, Spataro C, Zagato E, et al. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature; Published online 27 June 2018. https://doi.org 10.1038/s41586-018-0266-0