Prostate cancer rarely responds to immune-checkpoint blockade (ICB) therapies. Cancer-associated fibroblasts (CAF) are critical components of the immunologically “cold” tumor microenvironment and are considered a promising target to enhance the immunotherapy response. In this study, we aimed to reveal the mechanisms regulating CAF plasticity to identify potential strategies to switch CAFs from protumorigenic to antitumor phenotypes and to enhance ICB efficacy in prostate cancer. Integration of four prostate cancer single-cell RNA sequencing datasets defined protumorigenic and antitumor CAFs, and RNA-seq, flow cytometry, and a prostate cancer organoid model demonstrated the functions of two CAF subtypes. Extracellular matrix–associated CAFs (ECM-CAF) promoted collagen deposition and cancer cell progression, and lymphocyte-associated CAFs (Lym-CAF) exhibited an antitumor phenotype and induced the infiltration and activation of CD8+ T cells. YAP1 activity regulated the ECM-CAF phenotype, and YAP1 silencing promoted switching to Lym-CAFs. NF-κB p65 was the core transcription factor in the Lym-CAF subset, and YAP1 inhibited nuclear translocation of p65. Selective depletion of YAP1 in ECM-CAFs in vivo promoted CD8+ T-cell infiltration and activation and enhanced the therapeutic effects of anti-PD-1 treatment on prostate cancer. Overall, this study revealed a mechanism regulating CAF identity in prostate cancer and highlighted a therapeutic strategy for altering the CAF subtype to suppress tumor growth and increase sensitivity to ICB. Significance: YAP1 regulates cancer-associated fibroblast phenotypes and can be targeted to switch cancer-associated fibroblasts from a protumorigenic subtype that promotes extracellular matrix deposition to a tumor-suppressive subtype that stimulates antitumor immunity and immunotherapy efficacy.

Background and Aims: The aims of this study were to establish a maximum standardized uptake value (SUV_max) cutoff to discriminate clinically significant prostate cancer (csPCa) from benign prostate disease (BPD) by ⁶⁸Ga-labeled prostate-specific membrane antigen (⁶⁸Ga-PSMA-11) positron emission tomography/computed tomography (PET/CT) in patients with suspected prostate cancer (PCa), and to perform a prospective real-world validation of this cutoff value.

Evidence of more recent studies should be updated to evaluate the effect of long-term exposure to particulate matter (PM) on blood pressure and hypertension. Studies of long-term effects of PM₁, PM_2.5 and PM₁₀ on blood pressure (SBP, DBP, MAP), hypertension were searched in Pubmed, Web of Science and Embase before May, 2021. Meta-analysis of 41 studies showed that exposure to PM₁, PM_2.5 was associated with SBP (1.76 mmHg (95%CI:0.71, 2.80) and 0.63 mmHg (95%CI:0.40, 0.85), per 10 μg/m³ increase in PM), all three air pollutants (PM₁, PM_2.5, PM₁₀) was associated with DBP (1.16 mmHg (95%CI:0.34, 1.99), 0.31 mmHg (95%CI:0.16, 0.47), 1.17 mmHg (95%CI:0.24, 2.09), respectively. As for hypertension, PM₁, PM_2.5 and PM₁₀ were all significantly associated with higher risk of hypertension (OR=1.27 (95%CI:1.06, 1.52), 1.15 (95%CI:1.10, 1.20) and 1.11 (95%CI:1.07, 1.16). In conclusion, our study indicated a positive association between long-term exposure to particulate matter and increased blood pressure, hypertension.

Background: Cancer-associated fibroblasts (CAFs) promote tumor progression through extracellular matrix (ECM) remodeling and extensive communication with other cells in tumor microenvironment. However, most CAF-targeting strategies failed in clinical trials due to the heterogeneity of CAFs. Hence, we aimed to identify the cluster of tumor-promoting CAFs, elucidate their function and determine their specific membrane markers to ensure precise targeting.Methods: We integrated multiple single-cell RNA sequencing (scRNA-seq) datasets across different tumors and adjacent normal tissues to identify the tumor-promoting CAF cluster. We analyzed the origin of these CAFs by pseudotime analysis, and tried to elucidate the function of these CAFs by gene regulatory network analysis and cell-cell communication analysis. We also performed cell-type deconvolution analysis to examine the association between the proportion of these CAFs and patients’ prognosis in TCGA cancer cohorts, and validated that through IHC staining in clinical tumor tissues. In addition, we analyzed the membrane molecules in different fibroblast clusters, trying to identify the membrane molecules that were specifically expressed on these CAFs.Results: We found that COL11A1+ fibroblasts specifically exist in tumor tissues but not in normal tissues and named them cancer-specific fibroblasts (CSFs). We revealed that these CSFs were transformed from normal fibroblasts. CSFs represented a more activated CAF cluster and may promote tumor progression through the regulation on ECM remodeling and antitumor immune responses. High CSF proportion was associated with poor prognosis in bladder cancer (BCa) and lung adenocarcinoma (LUAD), and IHC staining of COL11A1 confirmed their specific expression in tumor stroma in clinical BCa samples. We also identified that CSFs specifically express the membrane molecules LRRC15, ITGA11, SPHK1 and FAP, which could distinguish CSFs from other fibroblasts.Conclusion: We identified that CSFs is a tumor specific cluster of fibroblasts, which are in active state, may promote tumor progression through the regulation on ECM remodeling and antitumor immune responses. Membrane molecules LRRC15, ITGA11, SPHK1 and FAP could be used as therapeutic targets for CSF-targeting cancer treatment.