Background: Prostate cancer is usually considered as immune “cold” tumor with poor immunogenic response and low density of tumor-infiltrating immune cells, highlighting the need to explore clinically actionable strategies to sensitize prostate cancer to immunotherapy. In this study, we investigated whether docetaxel-based chemohormonal therapy induces immunologic changes and potentiates checkpoint blockade immunotherapy in prostate cancer. Methods: We performed transcriptome and histopathology analysis to characterize the changes of prostate cancer immune microenvironment before and after docetaxel-based chemohormonal therapy. Furthermore, we investigated the therapeutic benefits and underlying mechanisms of chemohormonal therapy combined with anti-PD1 blockade using cellular experiments and xenograft prostate cancer models. Finally, we performed a retrospective cohort analysis to evaluate the antitumor efficacy of anti-PD1 blockade alone or in combination with docetaxel-based chemotherapy. Results: Histopathology assessments on patient samples confirmed the enrichment of tumor-infiltrating T cells after chemohormonal therapy. Moreover, we found that docetaxel activated the cGAS/STING pathway in prostate cancer, subsequently induced IFN signaling, resulting in lymphocytes infiltration. In a xenograft mouse model, docetaxel-based chemohormonal therapy prompted the intratumoral infiltration of T cells and upregulated the abundance of PD1 and PD-L1, thereby sensitizing mouse tumors to the anti-PD1 blockade. To determine the clinical significance of these results, we retrospectively analyzed a cohort of 30 metastatic castration-resistant prostate cancer patients and found that docetaxel combined with anti-PD1 blockade resulted in better prostate-specific antigen progression-free survival when compared with anti-PD1 blockade alone. Conclusions: Our study demonstrates that docetaxel activates the antitumoral immune response and facilitates T cell infiltration in a cGAS/STING-dependent manner, providing a combination immunotherapy strategy that would improve the clinical benefits of immunotherapy.
The androgen receptor (AR) signaling is a key contributor to tumorigenesis and the progression of prostate cancer. A subset of patients may develop neuroendocrine (NE) features, resulting in resistance to androgen deprivation therapy and poor prognosis. In this study, we combined immunostaining and bulk and single-cell transcriptome analyses to better characterize the status of AR in prostate cancer with neuroendocrine differentiation. The exploration of online datasets indicated the existence of ARHIGH/NEHIGH prostate cancer and revealed that these double-high cases are majorly present in castration-resistant prostate cancer with a less neuroendocrine-transdifferentiated state. We then reviewed 8,194 prostate cancer cases with available immunohistochemistry reports and found 2.3% cases (n = 189) that showed at least one of the NE markers (chromogranin A, synaptophysin, and neural cell adhesion molecule 1) being positive in at least 5% of epithelial cells. Within these 189 cases, we observed that 81.0% cases (n = 153) showed AR positive and 19.0% (n = 36) showed AR negative. Patients with AR loss tumors demonstrated a correlation with adverse clinical stages, indicating a trade-off between AR and advanced disease in neuroendocrine differentiation. Using multiplex immunofluorescence staining, we observed the co-localization of AR and NE markers in prostate cancer cells. In addition, data mining of single-cell transcriptome further confirmed the existence of ARHIGH/NEHIGH prostate cancer cells in castration-resistant samples and suggested that AR still exerts its androgen response and anti-apoptotic effect in these double-high cells. Thus, our study provides a better understanding of AR signaling in the cellular plasticity of prostate cancer with neuroendocrine differentiation and allows new insights into the therapeutic development.
Although several programmed cell death (PD)-1 inhibitors are approved for the first-line treatment of advanced urothelial carcinoma, their efficacy remains unknown in cisplatin-ineligible patients with upper tract urothelial carcinoma (UTUC) compared with gemcitabine plus carboplatin. Data for patients with UTUC were retrospectively retrieved from the electronic medical records of nine institutions between 2018 and 2021. Patients considered ineligible for cisplatin who received either PD-1 inhibitors (n = 70) or gemcitabine plus carboplatin (n = 53) were included. Efficacy was assessed using Response Evaluation Criteria in Solid Tumors. Median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. The objective response rate (ORR) was comparable between the PD-1 inhibitor and carboplatin–gemcitabine groups (38.6% versus 41.5%). Median PFS was 5.0 months (95% confidence interval [CI]: 2.0–8.0) in the PD-1 inhibitor group, versus 7.0 months (95% CI: 5.8–8.2) in the carboplatin–gemcitabine group (hazard ratio [HR] = 0.741, 95% CI: 0.485–1.132, p = .166). Median OS was 18 months (95% CI: 4.1–31.9) in the PD-1 inhibitor group, compared with 14 months (95% CI: 12.1–15.9) in the carboplatin–gemcitabine group (HR = 0.731, 95% CI: 0.426–1.256, p = .257). The duration of response was significantly longer in the PD-1 inhibitor group than in the carboplatin–gemcitabine group (not reached vs. 9 months, p < .001). Treatment-related adverse events were less frequent in the PD-1 inhibitor group than in the carboplatin–gemcitabine group (57.1% vs. 77.3%). In conclusion, PD-1 inhibitors displayed promising efficacy with less toxicity and longer DOR in the first-line treatment of UTUC in patients ineligible for cisplatin-based chemotherapy.
IntroductionNeuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer with poor prognosis and resistance to hormone therapy, which has limited therapeutic approaches. Therefore, this study aimed to identify a novel treatment for NEPC and provide evidence of its inhibitory effects.MethodsWe performed a high-throughput drug screening and identified fluoxetine, originally an FDA-approved antidepressant, as candidate therapeutic agent for NEPC. We carried out both in vitro and in vivo experiments to demonstrate the inhibitory effects of fluoxetine on NEPC models and its mechanism in detail.ResultsOur results demonstrated that fluoxetine effectively curbed the neuroendocrine differentiation and inhibited cell viability by targeting the AKT pathway. Preclinical test in NEPC mice model (PBCre4: Ptenf/f; Trp53f/f; Rb1f/f) showed that fluoxetine effectively prolonged the overall survival and reduced the risk of tumor distant metastases.DiscussionThis work repurposed fluoxetine for antitumor application, and supported its clinical development for NEPC therapy, which may provide a promising therapeutic strategy.
Introduction The effectiveness and safety of immune checkpoint inhibitor (ICI) monotherapy in advanced upper tract urothelial carcinoma (UTUC) is less reported. Methods In total, 106 consecutive advanced UTUC patients receiving ICI monotherapy were collected from nine high volume centers. Clinical outcomes were analyzed according to multiple parameters (e.g., treatment line, metastatic sites). Objective response rate (ORR), overall survival (OS) and progression‐free survival (PFS) were captured after ICI initiation. Results With a median follow‐up of 12.0 months, 25 patients in the first‐line group and 15 patients in the second‐line group died of UTUC. We reported a median OS of 18.0 months, a median PFS of 5.0 months, and an ORR of 38.6% for patients in the first‐line group; a median OS of 10.0 months, a median OS of 4.0 months, and an ORR of 27.8% for patients in the second‐line group. Complete response was observed in two patients in the first‐line group and one patient in the second‐line group with a total complete response rate of 2.8%. In the univariate and multivariate analysis, visceral metastasis with a hazard ratio of 2.4 was associate with poor OS. The most common treatment‐related adverse events included fatigue (11.3%), pruritus (10.4%), and diarrhea (6.6%). Conclusions This real‐world study suggests that ICI monotherapy is active and has acceptable toxic effects for unresectable or metastatic UTUC as first‐line therapy in cisplatin‐ineligible patients or second‐line therapy in platinum‐refractory patients.
Background: This study aimed to evaluate the effectiveness of 18 F-fluoro-2-deoxy-D-glucose Positron emission tomography/computed tomography ( 18 F-FDG PET/CT) in predicting prognosis and characterizing the intratumoral glucose uptake of neuroendocrine prostate cancer (NEPC). Methods: We retrospectively reviewed 189 NEPC patients from two medical centers between January 2009 and April 2021. Of these, 44 patients met the inclusion criteria. The maximum standardized uptake value (SUVmax) was measured to assess the metabolic state of NEPC and comparison were made between different histopathological subtypes. Kaplan-Meier and Cox regression analyses were performed to evaluate the predictive value of SUVmax on overall survival (OS) and progression-free survival (PFS).Results: This study analyzed 44 NEPC patients and found that 13 patients had small cell neuroendocrine carcinoma (SCNC), while 31 were diagnosed with adenocarcinoma with neuroendocrine differentiation (Ad-NED) based on histopathology, and a positive correlation was found between SUVmax and SCNC via Spearman correlation test (r s = 0.60, p < 0.0001). Furthermore, SUVmax demonstrated good diagnostic accuracy in differentiating SCNC from Ad-NED (area under the curve 0.88, 95% confidence interval [CI] 0.76-0.99). Kaplan-Meier survival analyses and univariate analyses revealed that patients with SUVmax > 10.2 had a significantly shorter OS than patients with SUVmax ≤ 10.2 (hazard ratio = 4.83, 95% CI 1.45-16.1, p = 0.01). Conclusions:The histopathological subtypes in NEPC showed a close correlation with the glucose metabolic activity of primary tumors as assessed by 18 F-FDG PET/
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