Abstract
Simple SummaryIn recent years, therapeutic options for patients with metastatic prostate cancer have improved significantly. However, the efficacy of current immunotherapy strategies in metastatic prostate cancer patients is limited. The prostate cancer tumor microenvironment, which includes immunosupressive cells such as tumor-associated macrophages, has been proposed as a major barrier to the effectiveness of immunotherapy. Thus, macrophages have emerged as a promising target to directly reduce tumor progression and overcome immunotherapy resistance. In this review we will summarize the current status of therapies targeting macrophages as well as their potential to increase immunotherapy efficacy in metastatic prostate cancer.Prostate cancer (PC) is the most common malignancy and the fifth cause of cancer death in men. The treatment for localized or locally advanced stages offers a high probability of cure. Even though the therapeutic landscape has significantly improved over the last decade, metastatic PC (mPC) still has a poor prognosis mainly due to the development of therapy resistance. In this context, the use of immunotherapy alone or in combination with other drugs has been explored in recent years. However, T-cell directed immune checkpoint inhibitors (ICIs) have shown limited activity with inconclusive results in mPC patients, most likely due to the highly immunosuppressive PC tumor microenvironment (TME). In this scenario, targeting macrophages, a highly abundant immunosuppressive cell type in the TME, could offer a new therapeutic strategy to improve immunotherapy efficacy. In this review, we summarize the growing field of macrophage-directed immunotherapies and discuss how these could be applied in the treatment of mPC, focusing on their combination with ICIs.
Highlights
It is well known that immunotherapy, and immune checkpoint inhibitors (ICIs) targeting the T-cell receptor–ligand interaction, such as cytotoxic lymphocyte antigen4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death ligand 1 (PDL1) [20], have made major advances in the last decade and are widely used in clinical practice to treat urological tumors [21], such as renal cell carcinoma [22] and urothelial cancer [23]
As previously stated, several clinical trials have evaluated the efficacy of ICIs in metastatic PC (mPC) patients who were not selected based on predictive molecular biomarkers, either as single agents or in combination with other checkpoint inhibitors or with other therapies with limited overall activity and inconclusive results [19,31]
The results demonstrated a median progression free survival (PFS) of 31.7 weeks in the treated and 22.7 weeks in the placebo arm, when used as maintenance therapy, tasquinimod efficiently reduced the risk of radiologic progression-free survival by 40% (NCT01732549) [127]
Summary
Prostate cancer (PC) is the most common malignancy in men and was the fifth cause of cancer death in males worldwide in 2020 [1]. It is important to note that several of these drugs, especially docetaxel and ARSIs, have been tested and approved in combination with ADT in earlier disease settings, including metastatic castration sensitive prostate cancer (mHSPC) [16,17,18] Despite these new therapeutic options, mCRPC still has a poor prognosis, with a median overall survival (OS) of approximately three years, mainly due to disease heterogeneity and the development of therapy resistance. To overcome these challenges, biomarker-based precision medicine approaches guiding the sequence of systemic therapy as well as new therapeutic strategies are needed. We further discuss the therapeutic potential of targeting TAMs to improve current immunotherapies in mPC
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