Scientists in the U.K., Switzerland, and Italy have shown how a type of immunotherapy that is undergoing trials for treating psoriasis also renders advanced prostate cancer responsive to hormone therapy. The researchers’ studies in human tissue and in a mouse model found that castration-resistant prostate cancer (CRCP) is driven by interleukin-23 (IL-23) produced by immune cells called myeloid-derived suppressor cells (MDSCs). Treating mice with androgen deprivation therapy (ADT)-resistant prostate tumors using an antibody that blocked IL-23 reactivated the tumors’ responsiveness to the androgen receptor antagonist (AR), enzalutamide (ENZA). Tumors shrank in mice receiving both the anti-IL-23 and enzalutamide therapy, and the animals also lived longer than control mice.

“Our study found an important interaction between hormone signaling and the immune system,” comments Johann de Bono, M.D. Regius Professor of Cancer Research at the Institute for Cancer Research (ICR) in London, which headed the studies in collaboration with colleagues at the Oncology Institute of Southern Switzerland and academic teams in Italy. “We believe we could exploit this to reverse hormone resistance in prostate cancer, and boost the effect of widely used prostate cancer drugs such as ENZA.…We are keen to start clinical trials to investigate how we can combine this new form of immunotherapy with existing hormone therapies, to improve treatment for men with advanced prostate cancer.” Dr. de Bono is also consultant medical oncologist at the Royal Marsden NHS Foundation Trust.

The ICR researchers, working with colleagues at the Oncology Institute of Southern Switzerland, and collaborators in Italy, report their findings in Nature, in a paper entitled “IL-23 Secreted by Myeloid Cells Drives Castration-Resistant Prostate Cancer.

Prostate cancer is the most commonly diagnosed cancer in men worldwide, and the second leading cancer-related cause of death, the authors write. Disease progression is promoted by androgens and androgen receptor signaling, and so ADT has become the primary form of treatment for patients with all stages of prostate cancer. However, many patients will eventually develop resistance to ADT and progress to more aggressive CRPC, which has a poor prognosis. 

Scientists don’t yet have a complete grasp of the mechanisms that underpin the development of resistance. “A better understanding of the mechanisms that drive CRPC could identify more effective therapies,” the team says. However, they state that “The well-established dependency of cancer cells on the tumour microenvironment suggests that the non-cancer-cell component of the tumour may control prostate cancer progression although the contribution of the tumour microenvironment, and in particular of the tumour immune response to the emergence of CRPC, remains unknown.”

To look in more detail at tumor microenvironment factors that might impact on the development of ADT resistance and CRPC, the team focused on MDSCs, a type of immune system cell that both the ICR team and independent researchers have previously shown homes in on the microenvironment of CRCP. Tumor-infiltrating MDSCs have, in addition, been found in patients with many different types of cancer, the researchers point out, while “MDSCs have also been found to be increased in patients that do not respond to ADT.” What isn't known, they note, is whether MDSCs support androgen-independent tumor growth and the emergence of CRPC.

Their initial studies showed higher numbers of polymorphonuclear (PMN)-type MDSCs in biopsied tumor samples from patients with CRPC, compared with biopsies from patients with castration-sensitive prostate cancer (CSPC). This finding wasn’t evidence that MDSCs were causally linked with the development of CRPC. To investigate this possibility, the team turned to a mouse model of prostate cancer in which surgical castration initially leads to tumor regression, but then after a period of weeks the tumors start to grow again and castration-resistant prostate tumors develop. Their experiments in these animals showed that MDSC numbers increased over time in parallel with the emergence of CRPC and represented the major subset of immune cells that were upregulated in the tumors following castration. These findings were validated in two separate mouse models.

Subsequent tests in mouse and in human prostate cancer cell lines showed that MDSCs effectively sustained cancer cell proliferation and survival under conditions of full androgen deprivation and boosted the transcription of AR target genes. “…these data demonstrated that MDSCs can regulate, in a paracrine manner, androgen-deprivation sensitivity in prostate tumour cells,” the authors write. Interestingly, exposing the CRPC model mice to a clinical-stage experimental CXCR2 antagonist, AZD5069, effectively blocked infiltration of tumors by MDSCs, and also halted progression of CRPC following castration. “Taken together, these data indicated that MDSCs are increased in CRPC and can promote proliferation of prostate tumour cells by sustaining AR signalling following androgen deprivation.”

Genetic analyses showed that the IL-23 gene was the most upregulated gene in tumors from castrated prostate cancer model mice, while cytokine profiling studies then confirmed that IL-23 was the most overexpressed factor produced by MDSCs. Analyses in the mouse model also confirmed that tumor-infiltrating MDSCs expressed IL-23 in vivo, “with PMN-MDSCs that infiltrated castration-resistant tumours expressing even higher levels of IL-23 compared to treatment-naive tumours,” they note. Levels of the IL-23 receptor were higher in tumor cells following castration in all of the mouse models studies.

Results from tests on human CRPC tumor biopsies largely replicated those of the mouse studies. In human tumors, tumor-infiltrating MDSCs expressed IL-23, the frequency of IL-23-producing tumor-infiltrating MDSCs was higher in the CRPC biopsies than in the CSPC biopsies, and plasma IL-23 levels were also elevated in patients with CRPC compared with CSPC patients. “Overall, these data demonstrate that IL-23 is increased in both mouse and human CRPCs, with IL-23 levels correlating with the number of tumor-infiltrating PMN-MDSCs.”

Encouragingly, mice with otherwise treatment-resistant tumors did respond to the standard CRPC hormone therapy ENZA, but only when they were also treated using an anti-IL-23 antibody. “…anti-IL-23 antibodies are currently being evaluated in clinical trials for the treatment of autoimmune diseases, including psoriasis, and are clinically well-tolerated,” the researchers note. Mice treated using hormone therapy plus anti-IL-23 exhibited normalization of prostate glands affected by the cancer, decreased tumor volume and proliferation, “robust inhibition” of AR activity, and the induction of tumor cell apoptosis. “Taken together, these data demonstrate that anti-IL-23 treatment can reverse resistance to castration in prostate cancer and enhance the efficacy of ENZA,” the researchers state.

“When we discovered that IL-23-producing MDSCs were the main immune subset infiltrating prostate tumors that have acquired resistance to hormone-treatment, we immediately realized that these cells could be one of the cause behind the emergence of castration-resistant prostate cancer,” comments Andrea Alimonti, M.D., professor of oncology at the Institute of Oncology Research, who is corresponding author of the team’s published paper. “This study describes a new unexpected mechanism by which the tumor immune response supports the growth of prostate cancer and it opens the way for future novel therapeutic applications for the treatment of metastatic prostate cancer patients.”

Previous data have demonstrated that MDSCs can support tumorigenesis in many cancers through different mechanisms, the authors note. However, “to our knowledge, the discovery described here, that IL-23 produced by MDSCs regulates resistance to castration in prostate cancer by sustaining AR signaling, was previously unknown, and adds novel mechanistic insights on how these immune cells support tumorigenesis.…In conclusion, we describe an alternative immunotherapeutic strategy for treating advanced prostate cancer that, unlike most other treatments, is not focused on re-activating the function of cytotoxic T lymphocytes against tumour cells….This work also shows that inhibition of IL-23 can reverse ADT resistance in men suffering from advanced prostate cancer.”

The team says it can foresee that immunotherapeutic strategies that target iL-23 in combination with established endocrine anticancer treatments will be “highly likely to improve treatment outcome for this common male cancer.”

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