IL-1β in Neoplastic Disease and the Role of Its Tumor-Derived Form in the Progression and Treatment of Metastatic Prostate Cancer

Abstract

Since its discovery, IL-1β has taken center stage as a key mediator of a very broad spectrum of diseases revolving around immuno-mediated and inflammatory events. Predictably, the pleiotropic nature of this cytokine in human pathology has led to the development of targeted therapeutics with multiple treatment indications in the clinic. Following the accumulated findings of IL-1β's central modulatory role in the immune system and the implication of inflammatory pathways in cancer, the use of IL-1β antagonists was first proposed and then also pursued for oncology disorders. However, this approach has consistently relied on the perceived need of interfering with IL-1β synthesized and secreted by immune cells. Herein, we discuss the importance of IL-1β derived from cancer cells which impacts primary tumors, particularly metastatic lesions, separately from and in addition to its more recognized role in immune-mediated inflammatory events. To this end, we focus on the instrumental contribution of IL-1β in the establishment and progression of advanced prostate adenocarcinoma. Special emphasis is placed on the potential role that the standard-of-care treatment strategies for prostate cancer patients have in unleashing IL-1β expression and production at metastatic sites. We conclude by reviewing the therapeutics currently used for blocking IL-1β signaling and propose a rationale for their concomitant use with standard-of-care treatments to improve the clinical outcomes of advanced prostate cancer.

Keywords: androgen deprivation therapies; androgen receptor; cytokines; metastasis.

Figure 1

IL-1β secretion in the prostate cancer bone metastatic niche. (1) Tumor cells lacking the AR secrete IL-1β, which causes (2) the release of soluble trophic factors via the activation of bone matrix resorption by osteoclasts and induces changes in the transcriptomic profile of bone mesenchymal stromal cells. (3) ADT/ARIs causes both an increase in AR-negative cancer cells and the inhibition of AR signaling and consequent de-repression and secretion of IL-1β from AR-positive tumor cells. These events lead to metastatic tumors harboring cancer cells heterogenous for AR expression or activity, but homogeneous for IL-1β production. Generated with Biorender.

Figure 2

Proposed biomarker-informed treatment of prostate cancer patients. Following successful treatment of locally confined prostate cancer by surgery and/or radiations, the plasma levels of prostate-specific antigens (PSA) decrease to undetectable levels. (1) A resurgence in PSA levels is defined as biochemical recurrence (BCR) and indicates the likelihood of minimal residual disease. Currently, BCR is treated with ADT, often combined with an ARI. We propose to (2) test patients for AR/IL-1β expression in circulating tumor cells (CTCs) collected from peripheral blood and for methylation of the IL-1β gene locus by collecting circulating DNA (ctDNA). Depending on the (3) methylation status of the IL-1β gene locus, patients with a methylated locus and therefore negative IL-1β expression would be treated with ADT alone (4a). Patients carrying an unmethylated IL-1β locus would be candidates for a combinatorial approach of ADT/ARIs plus inhibitors of IL-1β signaling (4b). Generated with Biorender.