Quantification and molecular correlates of tertiary lymphoid structures in primary prostate cancer.

OBJECTIVE: To morphologically describe tertiary lymphoid structures (TLS) in prostatectomy specimens and correlate them with clinical and transcriptomic features. METHODOLOGY: A total of 72 consecutive cases of entirely submitted radical prostatectomy (RP) patients tested with the Decipher Genomic Classifier were included in the study. Images were manually annotated using QuPath tools to denote tumor regions and each cluster of TLS. Clusters of lymphocytes that were surrounded on all four sides by tumor were defined as intra-tumor TLS (IT-TLS). Clusters of lymphocytes at the leading edge of carcinoma with either the prostatic pseudocapsule or benign parenchyma at one end were defined as peri-tumor TLS (PT-TLS). A classification algorithm to distinguish lymphocytes from non-lymphocytic cells using a supervised machine learning model was used. The associations between TLS formation and 265 gene expression-based signatures were examined. RESULTS: The magnitude of total TLS correlations with primary tumor gene expression signatures was moderate (~0.35-0.5) with several HLA, T-cell and B-cell Cluster signatures, showing positive correlation with various metrics for quantification of TLS. On the other hand, immune suppressive signatures (Treg, MDSC) were negatively correlated. While signatures for macrophages, NK cells and other immune cell types were uncorrelated for the most part. PT-TLS was associated with MHC signatures while IT TLS correlated with MHC and T-cell signatures. CONCLUSIONS: Clusters of inflammatory cells in the RP specimen can be divided spatially into PT TLS and IT-TLS, each with its unique molecular correlates of tumor immune microenvironment. The presence of TLS is positively correlated with MHC signatures, T- cell and B-cell cluster signatures but, negatively correlated with immune suppressive signatures. A subset of prostate cancer demonstrate a robust inflammatory response, and warrant further characterization in larger cohorts.

Prostate cancer research in the 21st century; report from the 2021 Coffey-Holden prostate cancer academy meeting.

INTRODUCTION: The 2021 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Prostate Cancer Research in the 21st Century," was held virtually, from June 24-25, 2021. METHODS: The CHPCA Meeting is organized by the Prostate Cancer Foundation as a unique discussion-oriented meeting focusing on critical topics in prostate cancer research envisioned to bridge the next major advances in prostate cancer biology and treatment. The 2021 CHPCA Meeting was virtually attended by 89 investigators and included 31 talks over nine sessions. RESULTS: Major topic areas discussed at the meeting included: cancer genomics and sequencing, functional genomic approaches to studying mediators of plasticity, emerging signaling pathways in metastatic castration resistant prostate cancer, Wnt signaling biology and the challenges of targeted therapy, clonal hematopoiesis, neuroendocrine cell plasticity and antitumor immunity, cancer immunotherapy and its synergizers, and imaging the tumor microenvironment and metabolism. DISCUSSION: This meeting report summarizes the research presented at the 2021 CHPCA Meeting. We hope that publication of this knowledge will accelerate new understandings and the development of new biomarkers and treatments for prostate cancer.

Long-term first-in-man Phase I/II study of an adjuvant dendritic cell vaccine in patients with high-risk prostate cancer after radical prostatectomy.

BACKGROUND: Patients with high-risk prostate cancer (PC) can experience biochemical relapse (BCR), despite surgery, and develop noncurative disease. The present study aimed to reduce the risk of BCR with a personalized dendritic cell (DC) vaccine, given as adjuvant therapy, after robot-assisted laparoscopic prostatectomy (RALP). METHODS: Twelve weeks after RALP, 20 patients with high-risk PC and undetectable PSA received DC vaccinations for 3 years or until BCR. The primary endpoint was the time to BCR. The immune response was assessed 7 weeks after surgery (baseline) and at one-time point during the vaccination period. RESULTS: Among 20 patients, 11 were BCR-free over a median of 96 months (range: 84-99). The median time from the end of vaccinations to the last follow-up was 57 months (range: 45-60). Nine patients developed BCR, either during (n = 4) or after (n = 5) the vaccination period. Among five patients diagnosed with intraductal carcinoma, three experienced early BCR during the vaccination period. All patients that developed BCR remained in stable disease within a median of 99 months (range: 74-99). The baseline immune response was significantly associated with the immune response during the vaccination period (p = 0.015). For patients diagnosed with extraprostatic extension (EPE), time to BCR was longer in vaccine responders than in non-responders (p = 0.09). Among 12 patients with the International Society of Urological Pathology (ISUP) grade 5 PC, five achieved remission after 84 months, and all mounted immune responses. CONCLUSION: Patients diagnosed with EPE and ISUP grade 5 PC were at particularly high risk of developing postsurgical BCR. In this subgroup, the vaccine response was related to a reduced BCR incidence. The vaccine was safe, without side effects. This adjuvant first-in-man Phase I/II DC vaccine study showed promising results. DC vaccines after curative surgery should be investigated further in a larger cohort of patients with high-risk PC.

Resolving the immune landscape of human prostate at a single-cell level in health and cancer.

The prostate gland produces prostatic fluid, high in zinc and citrate and essential for the maintenance of spermatozoa. Prostate cancer is a common condition with limited treatment efficacy in castration-resistant metastatic disease, including with immune checkpoint inhibitors. Using single-cell RNA-sequencing to perform an unbiased assessment of the cellular landscape of human prostate, we identify a subset of tumor-enriched androgen receptor-negative luminal epithelial cells with increased expression of cancer-associated genes. We also find a variety of innate and adaptive immune cells in normal prostate that were transcriptionally perturbed in prostate cancer. An exception is a prostate-specific, zinc transporter-expressing macrophage population (MAC-MT) that contributes to tissue zinc accumulation in homeostasis but shows enhanced inflammatory gene expression in tumors, including T cell-recruiting chemokines. Remarkably, enrichment of the MAC-MT signature in cancer biopsies is associated with improved disease-free survival, suggesting beneficial antitumor functions.

Arginine and Arginases Modulate Metabolism, Tumor Microenvironment and Prostate Cancer Progression.

Arginine availability and activation of arginine-related pathways at cancer sites have profound effects on the tumor microenvironment, far beyond their well-known role in the hepatic urea cycle. Arginine metabolism impacts not only malignant cells but also the surrounding immune cells behavior, modulating growth, survival, and immunosurveillance mechanisms, either through an arginase-mediated effect on polyamines and proline synthesis, or by the arginine/nitric oxide pathway in tumor cells, antitumor T-cells, myeloid-derived suppressor cells, and macrophages. This review presents evidence concerning the impact of arginine metabolism and arginase activity in the prostate cancer microenvironment, highlighting the recent advances in immunotherapy, which might be relevant for prostate cancer. Even though further research is required, arginine deprivation may represent a novel antimetabolite strategy for the treatment of arginine-dependent prostate cancer.

A Perspective on Withania somnifera Modulating Antitumor Immunity in Targeting Prostate Cancer.

Medicinal plants serve as a lead source of bioactive compounds and have been an integral part of day-to-day life in treating various disease conditions since ancient times. Withaferin A (WFA), a bioactive ingredient of Withania somnifera, has been used for health and medicinal purposes for its adaptogenic, anti-inflammatory, and anticancer properties long before the published literature came into existence. Nearly 25% of pharmaceutical drugs are derived from medicinal plants, classified as dietary supplements. The bioactive compounds in these supplements may serve as chemotherapeutic substances competent to inhibit or reverse the process of carcinogenesis. The role of WFA is appreciated to polarize tumor-suppressive Th1-type immune response inducing natural killer cell activity and may provide an opportunity to manipulate the tumor microenvironment at an early stage to inhibit tumor progression. This article signifies the cumulative information about the role of WFA in modulating antitumor immunity and its potential in targeting prostate cancer.

Using ex vivo culture to assess dynamic phenotype changes in human prostate macrophages following exposure to therapeutic drugs.

Within the prostate tumor microenvironment (TME) there are complex multi-faceted and dynamic communication occurring between cancer cells and immune cells. Macrophages are key cells which infiltrate and surround tumor cells and are recognized to significantly contribute to tumor resistance and metastases. Our understanding of their function in the TME is commonly based on in vitro and in vivo models, with limited research to confirm these model observations in human prostates. Macrophage infiltration was evaluated within the TME of human prostates after 72 h culture of fresh biopsies samples in the presence of control or enzalutamide. In addition to immunohistochemistry, an optimized protocol for multi-parametric evaluation of cellular surface markers was developed using flow cytometry. Flow cytometry parameters were compared to clinicopathological features. Immunohistochemistry staining for 19 patients with paired samples suggested enzalutamide increased the expression of CD163 relative to CD68 staining. Techniques to validate these results using flow cytometry of dissociated biopsies after 72 h of culture are described. In a second cohort of patients with Gleason grade group ≥ 3 prostate cancer, global macrophage expression of CD163 was unchanged with enzalutamide treatment. However, exploratory analyses of our results using multi-parametric flow cytometry for multiple immunosuppressive macrophage markers suggest subgroup changes as well as novel associations between circulating biomarkers like the neutrophil to lymphocyte ratio (NLR) and immune cell phenotype composition in the prostate TME. Further, we observed an association between B7-H3 expressing tumor-associated macrophages and the presence of intraductal carcinoma. The use of flow cytometry to evaluate ex vivo cultured prostate biopsies fills an important gap in our ability to understand the immune cell composition of the prostate TME. Our results highlight novel associations for further investigation.

Diacerein ameliorates testosterone-induced benign prostatic hyperplasia in rats: Effect on oxidative stress, inflammation and apoptosis.

Benign prostatic hypertrophy (BPH) is a serious medical condition among elderly male population. BPH pathogenesis has been linked to inflammation, cellular proliferation, oxidative stress and apoptosis. Diacerein (DIA) is a FDA approved anthraquinone drug that is used to treat joint diseases such as osteoarthritis. DIA has been studied for its potent anti-inflammatory and antioxidant effects, yet its role in managing BPH has not been investigated. In this study, DIA administration for two weeks at 50 mg/kg in testosterone-induced BPH rats significantly reduced prostate weight and index. Moreover, prostatic biochemical and structural features in BPH rats were significantly improved upon DIA treatment. Mechanistically, DIA treatment associated prostatic anti-hyperplastic effects were linked to downregulation of Nrf-2/HO-1 axis, downregulation of inflammatory TNF-a, IL-1ß, IL-6, downregulation of the cell proliferative marker PCNA and upregulation of caspase-3 levels. In addition, DIA treatment upregulated prostatic antioxidant GSH, the enzymatic SOD and CAT activities and reduced prostatic lipid peroxidation levels. Altogether, the present study provides evidence that DIA treatment might limit BPH progression via its potent anti-oxidant, anti-inflammatory, anti-proliferative and apoptosis inducing effects.

Cellular senescence as a possible link between prostate diseases of the ageing male.

Senescent cells accumulate with age in all tissues. Although senescent cells undergo cell-cycle arrest, these cells remain metabolically active and their secretome - known as the senescence-associated secretory phenotype - is responsible for a systemic pro-inflammatory state, which contributes to an inflammatory microenvironment. Senescent cells can be found in the ageing prostate and the senescence-associated secretory phenotype and can be linked to BPH and prostate cancer. Indeed, a number of signalling pathways provide biological plausibility for the role of senescence in both BPH and prostate cancer, although proving causality is difficult. The theory of senescence as a mechanism for prostate disease has a number of clinical implications and could offer opportunities for targeting in the future.

Flightless I Homolog Reverses Enzalutamide Resistance through PD-L1-Mediated Immune Evasion in Prostate Cancer.

Tumor cells can evade immune surveillance and immune killing during the emergence of endocrine therapy resistance in prostate cancer, but the mechanisms underlying this phenomenon are still unclear. Flightless I homolog (FLII) is a coregulator for transcription factors in several malignancies. Here, we have demonstrated that endocrine therapy resistance can induce an immunosuppressive prostate tumor microenvironment and immune evasion through FLII downregulation, which leads to activation of the YBX1/PD-L1 signaling pathway. FLII expression negatively correlated with expression of PD-L1 in tumors. Mechanism studies demonstrated that FLII physically interacted with YBX1 to inhibit nuclear localization of YBX1 and thereby suppress transcription of PDL1 in enzalutamide-resistant tumors. Restoration of FLII expression reversed enzalutamide resistance through activation of T-cell responses in the tumor microenvironment through inhibition of the YBX1/PD-L1 pathway. We also found that reversal of endocrine therapy resistance and immune evasion was mediated by proliferation of effector CD8+ T cells and inhibition of tumor infiltration by regulatory T cells and myeloid-derived suppressor cells. Taken together, our results demonstrate a functional and biological interaction between endocrine therapy resistance and immune evasion mediated through the FLII/YBX1/PD-L1 cascade. Combination therapy with FLII expression and endocrine therapy may benefit patients with prostate cancer by preventing tumor immune evasion.

Pattern recognition receptor-initiated innate immune responses in mouse prostatic epithelial cells‡.

Three major pathogenic states of the prostate, including benign prostatic hyperplasia, prostate cancer, and prostatitis, are related to the local inflammation. However, the mechanisms underlying the initiation of prostate inflammation remain largely unknown. Given that the innate immune responses of the tissue-specific cells to microbial infection or autoantigens contribute to local inflammation, this study focused on pattern recognition receptor (PRR)-initiated innate immune responses in mouse prostatic epithelial cells (PECs). Primary mouse PECs abundantly expressed Toll-like receptor 3 (TLR3), TLR4, TLR5, melanoma differentiation-associated protein 5 (MDA5), and IFN-inducible protein 16 (p204 in mouse). These PRRs can be activated by their respective ligands: lipopolysaccharide (LPS) and flagellin of Gram-negative bacteria for TLR4 and TLR5, polyinosinic-polycytidylic acid (poly(I:C)) for TLR3 and MDA5, and herpes simplex virus DNA analog (HSV60) for p204. LPS and flagellin predominantly induced the expression of inflammatory cytokines, including tumor necrosis factor alpha (TNFA), interleukin 6 (IL6), chemokines monocyte chemoattractant protein-1 (MCP1), and C-X-C motif chemokine 10 (CXCL10). Poly(I:C) and HSV60 predominantly induced the expression of type 1 interferons (IFNA and IFNB) and antiviral proteins: Mx GTPase 1, 2',5'-oligoadenylate synthetase 1, and IFN-stimulated gene 15. The replication of mumps virus in PECs was inhibited by type 1 IFN signaling. These findings provide insights into the mechanisms underlying innate immune response in the prostate.

Plasma cells are enriched in localized prostate cancer in Black men and are associated with improved outcomes.

Black men die more often of prostate cancer yet, interestingly, may derive greater survival benefits from immune-based treatment with sipuleucel-T. Since no signatures of immune-responsiveness exist for prostate cancer, we explored race-based immune-profiles to identify vulnerabilities. Here we show in multiple independent cohorts comprised of over 1,300 patient samples annotated with either self-identified race or genetic ancestry, prostate tumors from Black men or men of African ancestry have increases in plasma cell infiltrate and augmented markers of NK cell activity and IgG expression. These findings are associated with improved recurrence-free survival following surgery and nominate plasma cells as drivers of prostate cancer immune-responsiveness.

Pelvic floor muscles after prostate radiation therapy: morpho-functional assessment by magnetic resonance imaging, surface electromyography and digital anal palpation

ABSTRACT Aim: To evaluate the radiotherapy (RT) effect in the pelvic floor muscles (PFM) function in men with prostate cancer (PC). Materials and Methods: A cross-sectional study included three groups of patients with PC and RT indication: 1) Pre-RT group: evaluated before the beginning of RT; 2) Acute group: evaluated between six months and one year after RT; 3) Late Group: evaluated between two and a half years and four years post-RT. PFM assessment was divided into: a) functional assessment through the digital anal palpation (Modified Oxford Scale) and surface electromyography (sEMG) with anal probe; b) anatomical assessment by pelvic magnetic resonance imaging (MRI) with thickness measurements of levator ani muscle and pelvic specific parameters at rest and under Valsalva maneuver. We used Student t test, considering as significant p <0.05. Results: Thirty-three men were assessed: Pre-RT (n=12); Acute (n=10) and Late (n=11) groups. PFM functional assessment showed Late group with lower electromyographic activity, especially in the sustained contractions when compared to the Pre-RT (p=0.003) and Acute groups (p=0.006). There was no significant difference between groups in MRI. Conclusion: PFM functional assessment showed a decrease in sEMG activity in the Late group post-RT. Most of the sample (72.7%) did not know how to actively contract the PFM or had a weak voluntary contraction when assessed by digital anal palpation. Also, these patients presented higher prevalence of pelvic complaints. No changes were observed in the morpho-functional parameters evaluated by MRI, except the measurement of the membranous urethra length when comparing Pre-RT Group and Acute and Late Groups.

Large remodeling of the Myc-induced cell surface proteome in B cells and prostate cells creates new opportunities for immunotherapy.

MYC is a powerful transcription factor overexpressed in many human cancers including B cell and prostate cancers. Antibody therapeutics are exciting opportunities to attack cancers but require knowledge of surface proteins that change due to oncogene expression. To identify how MYC overexpression remodels the cell surface proteome in a cell autologous fashion and in different cell types, we investigated the impact of MYC overexpression on 800 surface proteins in three isogenic model cell lines either of B cell or prostate cell origin engineered to have high or low MYC levels. We found that MYC overexpression resulted in dramatic remodeling (both up- and down-regulation) of the cell surfaceome in a cell type-dependent fashion. We found systematic and large increases in distinct sets of >80 transporters including nucleoside transporters and nutrient transporters making cells more sensitive to toxic nucleoside analogs like cytarabine, commonly used for treating hematological cancers. Paradoxically, MYC overexpression also increased expression of surface proteins driving cell turnover such as TNFRSF10B, also known as death receptor 5, and immune cell attacking signals such as the natural killer cell activating ligand NCR3LG1, also known as B7-H6. We generated recombinant antibodies to these two targets and verified their up-regulation in MYC overexpression cell lines and showed they were sensitive to bispecific T cell engagers (BiTEs). Our studies demonstrate how MYC overexpression leads to dramatic bidirectional remodeling of the surfaceome in a cell type-dependent but functionally convergent fashion and identify surface targets or combinations thereof as possible candidates for cytotoxic metabolite or immunotherapy.

Comparative Genomics Reveals Distinct Immune-oncologic Pathways in African American Men with Prostate Cancer.

PURPOSE: The role of immune-oncologic mechanisms of racial disparities in prostate cancer remains understudied. Limited research exists to evaluate the molecular underpinnings of immune differences in African American men (AAM) and European American men (EAM) prostate tumor microenvironment (TME). EXPERIMENTAL DESIGN: A total of 1,173 radiation-naïve radical prostatectomy samples with whole transcriptome data from the Decipher GRID registry were used. Transcriptomic expressions of 1,260 immune-specific genes were selected to assess immune-oncologic differences between AAM and EAM prostate tumors. Race-specific differential expression of genes was assessed using a rank test, and intergene correlational matrix and gene set enrichment was used for pathway analysis. RESULTS: AAM prostate tumors have significant enrichment of major immune-oncologic pathways, including proinflammatory cytokines, IFNα, IFNγ, TNFα signaling, ILs, and epithelial-mesenchymal transition. AAM TME has higher total immune content score (ICSHIGH) compared with 0 (37.8% vs. 21.9%, P = 0.003). AAM tumors also have lower DNA damage repair and are genomically radiosensitive as compared with EAM. IFITM3 (IFN-inducible transmembrane protein 3) was one of the major proinflammatory genes overexpressed in AAM that predicted increased risk of biochemical recurrence selectively for AAM in both discovery [HRAAM = 2.30; 95% confidence interval (CI), 1.21-4.34; P = 0.01] and validation (HRAAM = 2.42; 95% CI, 1.52-3.86; P = 0.0001) but not in EAM. CONCLUSIONS: Prostate tumors of AAM manifest a unique immune repertoire and have significant enrichment of proinflammatory immune pathways that are associated with poorer outcomes. Observed immune-oncologic differences can aid in a genomically adaptive approach to treating prostate cancer in AAM.

Inhibitory Effect of Artemisinin on Testosterone Propionate Induced Benign Prostatic Hyperplasia.

BACKGROUND: Benign prostate hyperplasia [BPH] is an abnormal growth of prostate observed commonly in elderly males. Artemisinin has been reported to reduce the levels of testosterone. OBJECTIVE: This study is designed to evaluate the efficacy of Artemisinin on testosterone propionate [TP] induced benign prostate hyperplasia. MATERIALS AND METHODS: Male Wistar albino rats [n=24] were separated into four groups of six rats each. Group I served as control and distilled water using tween 80 as an emulsifying agent was administered subcutaneously. BPH was induced by testosterone propionate 3mg/kg [Group II], S.C. daily for 28 days. Group III was BPH + Finasteride treated group (10mg/kg orally for 28 days) and BPH + Artemisinin treated group (Group IV) (50 mg/kg orally for 28 days). RESULT: The study results showed significantly high levels of serum prostatic acid phosphatase (PAP), lactate dehydrogenase (LDH) and an elevation in prostate weight and prostatic index in Group II (BPH) when compared with Group I. The histopathological examination showed an increase in the epithelial proliferation of prostatic cells with involutions protruding into the lumen in BPH group when compared to the normal group. Treatment with Artemisinin (50 mg/kg) reduced the levels of PAP, LDH, prostate weight and prostatic index to a significant extent and restored the histoarchitectural features of the cells. CONCLUSION: The present study concludes that Artemisinin is efficacious in testosterone propionate induced BPH. This could be attributed, at least partly, to its anti-inflammatory property or its role in testosterone level reduction or as a Vitamin D receptor modulator.

IP-10 and CXCR3 signaling inhibit Zika virus replication in human prostate cells.

Our previous studies have shown that Zika virus (ZIKV) replicates in human prostate cells, suggesting that the prostate may serve as a long-term reservoir for virus transmission. Here, we demonstrated that the innate immune responses generated to three distinct ZIKV strains (all isolated from human serum) were significantly different and dependent on their passage history (in mosquito, monkey, or human cells). In addition, some of these phenotypic differences were reduced by a single additional cell culture passage, suggesting that viruses that have been passaged more than 3 times from the patient sample will no longer reflect natural phenotypes. Two of the ZIKV strains analyzed induced high levels of the IP-10 chemokine and IFNγ in human prostate epithelial and stromal mesenchymal stem cells. To further understand the importance of these innate responses on ZIKV replication, we measured the effects of IP-10 and its downstream receptor, CXCR3, on RNA and virus production in prostate cells. Treatment with IP-10, CXCR3 agonist, or CXCR3 antagonist significantly altered ZIKV viral gene expression, depending on their passage in cells of relevant hosts (mosquito or human). We detected differences in gene expression of two primary CXCR3 isoforms (CXCR3-A and CXCR3-B) on the two cell types, possibly explaining differences in viral output. Lastly, we examined the effects of IP-10, agonist, or antagonist on cell death and proliferation under physiologically relevant infection rates, and detected no significant differences. Although we did not measure protein expression directly, our results indicate that CXCR3 signaling may be a target for therapeutics, to ultimately stop sexual transmission of this virus.

Influence of Experimental Autoimmune Prostatitis on Sexual Function and the Anti-inflammatory Efficacy of Celecoxib in a Rat Model.

Experimental autoimmune prostatitis (EAP) is a well-established model induced by an autoimmune response to prostate antigen. The symptomatic, pathological, and immunological characteristics of EAP animals are highly consistent with human chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), which makes EAP an ideal model for this disease. Here, we investigate the influence of EAP on male rat sexual function and the efficacy of anti-inflammatory therapy with celecoxib. EAP rat models were established using male Wistar rats. Rats were randomly assigned to a normal control group, an EAP model group, or an EAP model with celecoxib treatment group (celecoxib group). Behavioral changes, sexual behavioral changes, and erectile function were estimated using an open-field test, a sucrose consumption test, mating experiments, and by intracavernous pressure/mean arterial pressure ratio (ICP/MAP). Histological changes in the prostate were observed by HE staining, and the serum inflammatory factors IL-1ß and TNF-α levels were measured by enzyme-linked immunosorbent assay. In addition, serotonin (5-hydroxytryptamine, 5-HT), 5-HT1A receptor, 5-HT2C receptor, and serotonin transporter (SERT) expression levels in the hippocampus and spinal cord (T13-L1, L5-S2) were examined by immunohistochemistry and western blot analysis. Results showed that EAP rats exhibited characteristics of depression, decreased sexual drive, premature ejaculation, and increased threshold of penile erection. Moreover, all these changes were effectively alleviated by celecoxib. Significant increases in prostatic interstitial infiltration by inflammatory cells and in serum IL-1ß and TNF-α levels were observed in EAP rats, and these were partially reduced by celecoxib. Additionally, the expression pattern of serotonin system regulators in the hippocampus and spinal cord were altered in EAP model rats, including a decrease in 5-HT levels and an increase in 5-HT1A receptor levels. In conclusion, autoimmune prostatitis impaired rat sexual function, and this was effectively prevented by anti-inflammatory therapy with celecoxib. Moreover, a serotonin system disorder in the central nervous system was likely mediated via inflammation in EAP rats.

The Immune System Fails to Mount a Protective Response to Gram-Positive or Gram-Negative Bacterial Prostatitis.

Bacterial prostatitis affects 1% of men, with increased incidence in the elderly. Acute bacterial prostatitis frequently progresses to chronicity, marked by recurrent episodes interspersed with asymptomatic periods of variable duration. Antibiotic treatment is standard of care; however, dissemination of antimicrobially resistant uropathogens threatens therapy efficacy. Thus, development of nonantibiotic-based approaches to treat chronic disease is a priority. Currently, why chronic prostatitis arises is unclear, as the immune response to prostate infection is incompletely understood. As 80% of prostatitis cases are caused by Gram-negative uropathogenic Escherichia coli (UPEC) or Gram-positive Enterococcus faecalis, we used a mouse transurethral instillation model to address the hypothesis that an innate immune response fails to develop following prostate infection with these uropathogens, leading to chronic disease. Surprisingly, infection induced robust proinflammatory cytokine expression and myeloid cell infiltration. Following a second infection, cytokine responses and innate cell infiltration were largely comparable to primary infection. Characteristic of memory responses, more lymphoid cells infiltrated the prostate in a second infection compared with a first, suggesting that adaptive immunity develops to eliminate the pathogens. Unexpectedly, bacterial burden in prostates challenged with either UPEC or E. faecalis was equal or greater than primary infection despite that a protective adaptive response to UPEC infection was evident in the bladder of the same animals. Our findings support that chronic or recurrent prostatitis develops despite strong innate immune responses and may be the result of a failure to develop immune memory to infection, pointing to actionable targets for immunotherapy.

The assessment of a possible link between HPV-mediated inflammation, apoptosis, and angiogenesis in Prostate cancer.

BACKGROUND: The aim of this study was to determine the presence of HPV in patients with Prostate cancer (PCa) and its possible association with cancer progression. METHODS: In this case-control study, fresh prostate tissues and blood samples were collected from 90 individuals, including 58 cases samples with PCa and 32 non-malignant prostate tissue samples as a control group. The expression level of viral genes (E2, E6, and E7) and cellular factors including tumor suppressor proteins (Rb and p53), anti-apoptotic mediators (Bcl-2 and survivin), and some mediators involved in inflammation and angiogenesis was evaluated. RESULTS: The presence of the HPV genome was identified in 19 out of the 58 cases (32.7%) and five out of the 32 controls (15.6%). However, there was not any statistically significant relationship between the presence of the HPV genome and PCa (OR = 2.63, 95% C.I = 0.89-7.91, P-value = 0.078). Moreover, the HPV high-risk genotypes 16 and 18 were detected in 47.4% and 31.6% of HPV-infected PCa tissues, respectively. The expression level of the tumor suppressor proteins (Rb and p53) significantly decreased in the HPV-infected samples compared to the HPV negative specimens (P-value = 0.01, P-value = 0.01, respectively). However, the expression level of the anti-apoptotic mediators and those involved in angiogenesis and inflammation significantly increased in the HPV-infected PCa group compared to the HPV-negative PCa and control groups (P-value < 0.05, respectively). CONCLUSION: Our study suggests that although it is not definitely known whether HPV causes PCa, this virus probably modulates PCa cell behavior by affecting inflammation, angiogenesis, and apoptosis mechanisms, which, in turn, promotes tumorigenesis.