Abstract
Simple SummaryImmunotherapy has changed the landscape of treatment modalities available for many different types of malignancies. However, the factors that influence the success of immunotherapeutics have not been as clearly seen in advanced prostate cancer, likely due to immunosuppressive factors that exist within the prostate cancer tumor microenvironment. While there have been many immunotherapeutics used for prostate cancer, the majority have targeted a single immunosuppressive mechanism resulting in limited clinical efficacy. More recent research centered on elucidating the key mechanisms of immune resistance in the prostate tumor microenvironment has led to the discovery of a range of new treatment targets. With that in mind, many clinical trials have now set out to evaluate combination immunotherapeutic strategies in patients with advanced prostate cancer, in the hopes of circumventing the immunosuppressive mechanisms.The use of immunotherapy has become a critical treatment modality in many advanced cancers. However, immunotherapy in prostate cancer has not been met with similar success. Multiple interrelated mechanisms, such as low tumor mutational burden, immunosuppressive cells, and impaired cellular immunity, appear to subvert the immune system, creating an immunosuppressive tumor microenvironment and leading to lower treatment efficacy in advanced prostate cancer. The lethality of metastatic castrate-resistant prostate cancer is driven by the lack of therapeutic regimens capable of generating durable responses. Multiple strategies are currently being tested to overcome immune resistance including combining various classes of treatment modalities. Several completed and ongoing trials have shown that combining vaccines or checkpoint inhibitors with hormonal therapy, radiotherapy, antibody–drug conjugates, chimeric antigen receptor T cell therapy, or chemotherapy may enhance immune responses and induce long-lasting clinical responses without significant toxicity. Here, we review the current state of immunotherapy for prostate cancer, as well as tumor-specific mechanisms underlying therapeutic resistance, with a comprehensive look at the current preclinical and clinical immunotherapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and impaired cellular immunity that have largely limited the utility of immunotherapy in advanced prostate cancer.
Highlights
Androgens have a key role in the pathogenesis of prostate cancer (PCa), and treatment modalities altering androgen receptor signaling pathways are the standard of care for advanced and disseminated disease
Major Histocompatibility Complex (MHC) Class I proteins are typically found on the cell surface and have an important anti-tumor role presenting tumor antigens to cytotoxic T lymphocytes (CTL) resulting in an immunostimulatory signaling cascade leading to T cell activation and target cell destruction [8,26]
One study found mean somatic mutational rates at a frequency of 0.9 per megabase, approximately 10 times lower than reported for melanoma [29]. This highlights a potential lack of T-cell co-stimulation and activation in the PCa tumor microenvironment (TME), which prohibits the generation of a powerful adaptive immune response following antigen presentation; a key step in immunotherapy effectiveness [8]
Summary
Androgens have a key role in the pathogenesis of prostate cancer (PCa), and treatment modalities altering androgen receptor signaling pathways are the standard of care for advanced and disseminated disease. Utilizing the immune system to treat cancer has been a revolutionary development and has quickly become the standard treatment for many cancer types, superseding other targeted and systemic therapies [3]. With regard to PCa, the interaction between prostatic epithelial cells and the immune and non-immune cells that make up the tumor microenvironment (TME) have been shown to have an important role in the complex changes that occur and result in disease progression, development of resistant metastases, and the overall resistance to both conventional and experimental therapies [1,5]. We set out to identify and explore key immune resistance mechanisms that lead to treatment failure in the immunosuppressive TME of PCa, and focus on therapeutic strategies (Figure 1) and approaches that target the immunosuppressive TME and seek to overcome these resistance mechanisms
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