Potential Role of Acetylpolyamines in the Prostatic Tumor Microenvironment

Abstract

Prostate cancer is the most common cancer in men excluding non-melanoma skin cancer, and the second leading cause of cancer-related mortality after lung cancer. Early stages of prostate cancer are dependent on androgen for proliferation and survival, and can be curable with standard surgical or radiation treatment options. Unfortunately, recurrent and metastatic prostate cancer is highly refractory. Eventually the disease will develop castration resistance which is incurable with our currently available androgen deprivation therapies and chemotherapies. Initially, immunotherapy in preclinical trials showed promise in activating the innate and adaptive immune system to target prostate cancer cells. While sipuleucel-T and pembrolizumab have been approved by the FDA for the treatment of asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer patients, immunotherapies have overall shown only modest efficacy in clinical practice. Prostate tumors are heterogeneous and considered an immunologically “cold” tumor due to low expression of neoantigens and low tumor mutational burden, creating a significant obstacle to treatment with immunotherapy. In addition, the prostatic tumor microenvironment secretes factors that recruit an abundance of anti-inflammatory tumor associated macrophages (TAM), increases regulatory T cell infiltration, and activates immature myeloid cell differentiation to myeloid derived suppressor cells. These cells create an immunosuppressive barrier which inactivates cytotoxic T cells and prevents natural killer cell permeability. As of yet, we are unable to explain the abundance of infiltrating tumor associated macrophages associated with metastatic prostate cancer tumors. One factor may be acetylated polyamines released by prostate cancer cells into the tumor microenvironment. Classically, literature reports decreased total intracellular polyamine concentration with prostate cancer progression, suggesting polyamines have anti-tumorigenic properties. However, aggressive prostate cancer cells are shown to have a significant elevation in the message, protein, and activity of enzymes that direct polyamine metabolism. Interestingly, major studies that report decreased total polyamines levels in prostate cancer do not take into consideration the acetylated forms of these molecules, which is an alteration necessary for polyamine efflux and catabolism. Therefore, it would be reasonable to discuss how dysregulated polyamine metabolism in prostate cancer cells likely results in increased acetylpolyamines, as this may provide new insights into potential roles of these molecules in the prostatic tumor microenvironment. This review will focus on common mutations in prostate cancer that increase enzymes involved in polyamine synthesis and acetylation, reported impact polyamines have on varying mechanisms in immune cells that promote an immunosuppressive milieu, and highlight possible therapeutic targets that could increase the efficacy of currently available immunotherapies.