Microbes hijack prostate cancer therapy Androgens such as testosterone and dihydrotestosterone are essential for male reproduction and sexual function. Androgens can also influence the growth of prostate tumor cells, and androgen deprivation therapy (ADT) either by surgical means (castration) or pharmacological approaches (hormone suppression), is the cornerstone of current prostate cancer treatments. Pernigoni et al . found that when the body was deprived of androgens during ADT, the gut microbiome could produce androgens from androgen precursors (see the Perspective by McCulloch and Trinchieri). Gut commensal microbiota in ADT-treated patients or castrated mice produced androgens that were absorbed into the systemic circulation. These microbe-derived androgens appeared to favor the growth of prostate cancer and helped to facilitate development into a castration- or endocrine therapy–resistant state. —PNK

Summary Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment supporting tumorigenesis. TAMs re-education has been proposed as a strategy to promote tumor inhibition. However, whether this approach may work in prostate cancer is unknown. Here we find that Pten -null prostate tumors are strongly infiltrated by TAMs expressing C-X-C chemokine receptor type 2 (CXCR2), and activation of this receptor through CXCL2 polarizes macrophages toward an anti-inflammatory phenotype. Notably, pharmacological blockade of CXCR2 receptor by a selective antagonist promoted the re-education of TAMs toward a pro-inflammatory phenotype. Strikingly, CXCR2 knockout monocytes infused in Pten pc−/− ; Trp53 pc−/− mice differentiated in tumor necrosis factor alpha (TNF-α)-releasing pro-inflammatory macrophages, leading to senescence and tumor inhibition. Mechanistically, PTEN -deficient tumor cells are vulnerable to TNF-α-induced senescence, because of an increase of TNFR1 . Our results identify TAMs as targets in prostate cancer and describe a therapeutic strategy based on CXCR2 blockade to harness anti-tumorigenic potential of macrophages against this disease.

Background Serum prostate‐specific antigen (PSA) may predict the risk of positive positron emission tomography/computed tomography with radiolabelled prostate‐specific membrane antigen (PSMA‐PET/CT) in patients with biochemical recurrent prostate cancer (BRPCa). However, to date, there are no clear data regarding the correlation between PSA kinetics and PSMA‐PET findings. We performed a systematic review and meta‐analysis to provide evidence‐based data in this setting. Methods A comprehensive literature search of studies published through October 2018 in PubMed/MEDLINE, EMBASE and Cochrane library databases was performed. A meta‐analysis to establish the detection rate (DR) of PSMA‐PET using different cut‐off values of PSA doubling time (PSAdt) and a pooled analysis to establish whether shorter PSAdt may predict positive PSMA‐PET results was performed in patients with BRPCa. Results Twelve articles were included in the systematic review, and eight articles (including about 1400 patients) were selected for the meta‐analysis. The pooled DR including 95% confidence intervals (95%CI) of PSMA‐PET in restaging prostate cancer (PCa) patients was 72% (95%CI:60%‐82%), increasing to 83% (95%CI:75%‐90%) when PSAdt was ≤6 months and decreasing to 60% (95%CI:37%‐80%) when PSAdt was >6 months, without a statistical significant difference. PSAdt ≤6 months may predict the positive result of PSMA‐PET (pooled odds ratio: 3.22; 95%CI:1.17‐8.88). Statistical heterogeneity among the included studies was found. Conclusions PSA kinetics, and in particular shorter PSAdt, may be predictor of PSMA‐PET positivity in patients with BRPCa. Further larger studies in this setting are warranted.

In the last 10 years, many new therapeutic options have been approved in advanced prostate cancer (PCa) patients, granting a more prolonged survival in patients with metastatic disease, which, nevertheless, remains incurable. The emphasis on immune checkpoint inhibitors (ICIs) has led to many trials in this setting, with disappointing results until now. Therefore, we discuss the immunobiology of PCa, presenting ongoing trials and the available clinical data, to understand if immunotherapy could represent a valid option in this disease, and which subset of patients may be more likely to benefit. Current evidence suggests that the tumor microenvironment needs a qualitative rather than quantitative evaluation, along with the genomic determinants of prostate tumor cells. The prognostic or predictive value of immunotherapy biomarkers, such as PD-L1, TMB, or dMMR/MSI-high, needs further evaluation in PCa. Monotherapy with immune checkpoint inhibitors (ICIs) has been modestly effective. In contrast, combined strategies with other standard treatments (hormonal agents, chemotherapy, PARP inhibitors, radium-223, and TKIs) have shown some results. Immunotherapy should be better investigated in biomarker-selected patients, particularly with specific pathway aberrations (e.g., AR-V7 variant, HRD, CDK12 inactivated tumors, MSI-high tumors). Lastly, we present new possible targets in PCa that could potentially modulate the tumor microenvironment and improve antitumor activity with ICIs.