Targeting MAO offers a novel immunotherapeutic strategy for prostate cancer by modulating the "tumor-stroma-immune" interaction network.

There is growing evidence for the role of inflammation in prostate cancer (PCa) progression, although the precise role of inflammation in the context of androgen ablation therapy remains unclear. Various reports demonstrate that androgen deprivation results in an increased inflammatory response in PCa and also suggest a potential role of inflammatory cells, such as macrophages and B-cells, in the acquisition of castration-resistant prostate cancer (CRPC). New PCa therapeutics have emerged showing great promise in clinical trials, such as the second generation androgen receptor (AR) antagonist MDV3100 (MDV). MDV has been shown to be more potent and effective in delaying tumor progression in CRPC patients compared to the commonly used first generation antagonist bicalutamide. However, acquired resistance to MDV has begun to emerge in preclinical models. A great deal of attention has been focused on the tumor-cell instrinsic AR bypass as the key mechanism of therapeutic resistance or failure. Few studies have explored the possible roles of tumor microenvironment in modulating therapeutic response. We and others have shown that tumor-associated macrophages (TAMs) can modulate PCa progression and therapeutic resistance. The recruitment of macrophages to and their functions in the tumor is recognized to be critically dependent on the macrophage colony-stimulating factor-1 (M-CSF-1, CSF-1), signaling through its receptor, CSF1R. Exploiting this fact, we used a selective CSF1R inhibitor, GW2580, to block TAMs influx and showed that they contribute to PCa progression and therapeutic resistance. In this current study, we observed a high level of TAMs infiltrating the CSF-1-expressing Myc-CaP murine prostate tumors. Additionally, MDV treatment further increased the level of CSF-1 expressed in tumors, further boosting the infiltration of TAMs which was reversed by GW2580. We have also observed increased expression of matrix-remodeling and pro-angiogenic factors, MMP-9 and VEGF-A in macrophages treated with conditioned media from MDV-treated Myc-CaP cells in vitro and in MDV-treated Myc-CaP tumors in vivo. These results lead us to hypothesize that blocking the CSF-1/CSF1R axis in combination with MDV anti-AR therapy, could result in synergistic anti-tumor effects. Indeed our preliminary studies indicate the combined therapies achieve slightly more effective tumor growth suppression than either of the single therapies. Our data suggest that infiltrating TAMs are alternatively activated (M2-skewed), which have been demonstrated to promote tumor growth and metastasis in many cancers. Our results suggest that TAMs in the prostatic microenvironment contribute to PCa progression and therapeutic resistance. The rational combined targeted therapy pursued here holds promise to improve the long term-efficacy of new PCa therapeutics such as MDV, and ultimately increase overall survival of prostate cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C226.

Hormonal therapy of prostate cancer, by inhibiting androgen production and/or androgen function, is the treatment of choice for advanced prostate cancer. Although most patients respond initially, the effect is only temporary, and the tumor cells will resume proliferation in an androgen-deprived environment. The mechanism for androgen-independent proliferation of cancer cells is unclear. Hormonal therapy induces neuroendocrine differentiation of prostate cancer cells, which is hypothesized to contribute to tumor recurrence by a paracrine mechanism. We studied signal transduction pathways of neuroendocrine differentiation in LNCaP cells after androgen withdrawal, and we showed that both the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway and ERK are activated, but only the former is required for neuroendocrine differentiation. A constitutively active AKT promotes neuroendocrine differentiation and a dominant negative AKT inhibits it. Activation of AKT by IGF-1 leads to neuroendocrine differentiation, and neuroendocrine differentiation induced by epinephrine requires AKT activation. We also show that the AKT pathway is likely responsible for neuroendocrine differentiation in DU145, an androgen-independent prostate cancer cell line. Therefore, our study demonstrated a novel function of the AKT pathway in prostate cancer progression and identified potential targets that may be explored for the treatment of androgen-independent cancer.

Monoamine oxidase A (MAOA): A promising target for prostate cancer therapy

Targeting TCTP as a New Therapeutic Strategy in Castration-resistant Prostate Cancer

e17537 Background: A significant proportion of men with Prostate Cancer (PCa) develop castration resistant prostate cancer (CRPC) and do not respond to hormonal agents that decrease androgens. In trying to understand the causes of androgen resistance that develop in CRPC, it is considered most relevant to study the role of Androgen receptor (AR) in the development and progression of PCa from androgen dependent to androgen independent state. Recent studies have highlighted the significance of tumor microenvironment (TME) in regulation of PCa progression in addition to AR. A key molecule in the regulation of TME interactions is nitric oxide (NO). We have shown in our recent study, the critical association of NO with the TME in CRPC. However, the effects of NO to modulate the progression of PCa to CRPC with respect to AR still remains largely unexplored. Methods: 22RV1, LNCaP, LNCaPAPIPC(cells expressing no AR), and LNCaPshAR/pATK (cells expressing low AR), cells were used for the study. Cell proliferation was first assessed by MTT assay. The castrated SCID mice were grafted with 22RV1 cells and were treated with GSNO at the dosage of 10mg/kg/day IP. After treatment, animals were humanely sacrificing. Tumor RNA and proteins were analysed for markers that are important for PCa progression using qPCR, western blot and cytokine antibody array. Animal experiments were carried out in compliance with the IACUC of University of Miami. GraphPad Prism (GraphPad Software) was used for statistical analysis. Results: In addition to reducing the tumor burden, the expression of anti-inflammatory (M2) macrophages (CD206 and Arginase1) is decreased and that of the pro-inflammatory (M1) macrophage (iNOS) is increased in mice which received increased NO levels. Furthermore, to study the effects of NO on progression of PCa from androgen dependent to androgen independent stage, we characterized the LNCAP cell models with differential extent of AR knockdown (LNCaP, LNCaPshAR/pATK and LNCaPAPIPC) for the effects of increased NO levels. Results showed that NO had significant impact on cell proliferation on androgen dependent PCa cells however the effects were negligible in cells expressing low or no AR, suggesting that effects of NO on PCa cell proliferation are AR dependent. Conclusions: Our results suggest that during PCa progression, NO suppresses TAMs to target the TME in an AR dependent manner. Further studies are undergoing to establish the impacts of NO in PCa progression.

BackgroundProstate cancer (PCa) is a leading malignancy with a rising global incidence, posing significant challenges in treatment. The immunosuppressive tumor microenvironment (TME) in castration-resistant prostate cancer (CRPC) is a major barrier to effective immunotherapy. Identifying therapeutic targets that modulate the immune response within TME is crucial for advancing PCa treatment.Materials and methodsIn this study, we employed Mendelian randomization (MR) to investigate the causal relationships between gene expression of blood proteins and PCa risk. We utilized cis-eQTL data from the eQTLGen Consortium and immune cell phenotype data from the NHGRI-EBI GWAS Catalog. Our analysis included primary and secondary cohorts, totaling over 800,000 individuals. Colocalization analysis was performed to confirm the genetic associations, and mediation MR analysis was used to explore the mediating role of proteins in tumor immunity. Drug prediction and molecular docking were applied to assess the potential of identified targets as druggable candidates.ResultsOur MR analysis identified 557 proteins associated with PCa in the primary cohort, with 85 proteins remaining significant in another independent cohort. Mediation analysis revealed nine proteins that mediated the impact of immune cells on PCa. Colocalization analysis confirmed the causality of five proteins, which were further supported by phenome-wide association studies (PheWAS) and protein–protein interaction (PPI) networks. Molecular docking demonstrated strong binding affinity of potential drugs to these targets.ConclusionsThis study identified five drug targets in prostate cancer that modulate the tumor immune response. These targets may expedite drug development and personalize medicine, potentially enhancing treatment efficacy and reducing side effects.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12672-025-02985-3.

<div>Abstract<p><b>Purpose:</b> Androgen deprivation therapy (ADT), including enzalutamide, induces resistance in prostate cancer; ADT resistance is associated with neuroendocrine differentiation (NED) and tumor-associated macrophages (TAM). This study aimed to investigate the association between enzalutamide-induced NED and TAMs and its mechanism.</p><p><b>Experimental Design:</b> The association between enzalutamide-induced NED and TAMs was investigated by IHC using prostate cancer tissues, enzalutamide-resistant mouse xenografts, and a coculture system. The underlying mechanisms were assessed using <i>in vitro</i> cytokine antibody arrays, ELISAs, chromatin immunoprecipitation, and other methods. An orthotopic prostate cancer mouse model was established to evaluate the <i>in vivo</i> effects of combined IL6 receptor (IL6R) and high mobility group box 1 (HMGB1) inhibition on enzalutamide resistance.</p><p><b>Results:</b> High CD163 expression was observed in ADT-treated prostate cancer or castration-resistant prostate cancer (CRPC) tissues with high levels of neuron-specific enolase (NSE) and chromogranin A (CHGA) and in enzalutamide-resistant xenografts, indicating the crucial roles of NED and TAMs in enzalutamide resistance. Specifically, enzalutamide-induced HMGB1 expression facilitated TAM recruitment and polarization and drove NED via β-catenin stabilization. HMGB1-activated TAMs secreted IL6 to augment enzalutamide-induced NED and directly promote HMGB1 transcription via STAT3. Finally, inhibition of the IL6/STAT3 pathway by tocilizumab combined with HMGB1 knockdown inhibited enzalutamide-induced resistance in an orthotopic prostate cancer mouse model.</p><p><b>Conclusions:</b> Enzalutamide elevates HMGB1 levels, which recruits and activates TAMs. Moreover, IL6 secreted by HMGB1-activated TAMs facilitates the enzalutamide-induced NED of prostate cancer, forming a positive feedback loop between NED in prostate cancer and TAMs. The combined inhibition of IL6R and HMGB1 may serve as a new treatment for enzalutamide resistance in patients with advanced or metastatic prostate cancer. <i>Clin Cancer Res; 24(3); 708–23. ©2017 AACR</i>.</p></div>

Purpose: Androgen deprivation therapy (ADT), including enzalutamide, induces resistance in prostate cancer; ADT resistance is associated with neuroendocrine differentiation (NED) and tumor-associated macrophages (TAM). This study aimed to investigate the association between enzalutamide-induced NED and TAMs and its mechanism.Experimental Design: The association between enzalutamide-induced NED and TAMs was investigated by IHC using prostate cancer tissues, enzalutamide-resistant mouse xenografts, and a coculture system. The underlying mechanisms were assessed using in vitro cytokine antibody arrays, ELISAs, chromatin immunoprecipitation, and other methods. An orthotopic prostate cancer mouse model was established to evaluate the in vivo effects of combined IL6 receptor (IL6R) and high mobility group box 1 (HMGB1) inhibition on enzalutamide resistance.Results: High CD163 expression was observed in ADT-treated prostate cancer or castration-resistant prostate cancer (CRPC) tissues with high levels of neuron-specific enolase (NSE) and chromogranin A (CHGA) and in enzalutamide-resistant xenografts, indicating the crucial roles of NED and TAMs in enzalutamide resistance. Specifically, enzalutamide-induced HMGB1 expression facilitated TAM recruitment and polarization and drove NED via β-catenin stabilization. HMGB1-activated TAMs secreted IL6 to augment enzalutamide-induced NED and directly promote HMGB1 transcription via STAT3. Finally, inhibition of the IL6/STAT3 pathway by tocilizumab combined with HMGB1 knockdown inhibited enzalutamide-induced resistance in an orthotopic prostate cancer mouse model.Conclusions: Enzalutamide elevates HMGB1 levels, which recruits and activates TAMs. Moreover, IL6 secreted by HMGB1-activated TAMs facilitates the enzalutamide-induced NED of prostate cancer, forming a positive feedback loop between NED in prostate cancer and TAMs. The combined inhibition of IL6R and HMGB1 may serve as a new treatment for enzalutamide resistance in patients with advanced or metastatic prostate cancer. Clin Cancer Res; 24(3); 708-23. ©2017 AACR.

<div>Abstract<p><b>Purpose:</b> Androgen deprivation therapy (ADT), including enzalutamide, induces resistance in prostate cancer; ADT resistance is associated with neuroendocrine differentiation (NED) and tumor-associated macrophages (TAM). This study aimed to investigate the association between enzalutamide-induced NED and TAMs and its mechanism.</p><p><b>Experimental Design:</b> The association between enzalutamide-induced NED and TAMs was investigated by IHC using prostate cancer tissues, enzalutamide-resistant mouse xenografts, and a coculture system. The underlying mechanisms were assessed using <i>in vitro</i> cytokine antibody arrays, ELISAs, chromatin immunoprecipitation, and other methods. An orthotopic prostate cancer mouse model was established to evaluate the <i>in vivo</i> effects of combined IL6 receptor (IL6R) and high mobility group box 1 (HMGB1) inhibition on enzalutamide resistance.</p><p><b>Results:</b> High CD163 expression was observed in ADT-treated prostate cancer or castration-resistant prostate cancer (CRPC) tissues with high levels of neuron-specific enolase (NSE) and chromogranin A (CHGA) and in enzalutamide-resistant xenografts, indicating the crucial roles of NED and TAMs in enzalutamide resistance. Specifically, enzalutamide-induced HMGB1 expression facilitated TAM recruitment and polarization and drove NED via β-catenin stabilization. HMGB1-activated TAMs secreted IL6 to augment enzalutamide-induced NED and directly promote HMGB1 transcription via STAT3. Finally, inhibition of the IL6/STAT3 pathway by tocilizumab combined with HMGB1 knockdown inhibited enzalutamide-induced resistance in an orthotopic prostate cancer mouse model.</p><p><b>Conclusions:</b> Enzalutamide elevates HMGB1 levels, which recruits and activates TAMs. Moreover, IL6 secreted by HMGB1-activated TAMs facilitates the enzalutamide-induced NED of prostate cancer, forming a positive feedback loop between NED in prostate cancer and TAMs. The combined inhibition of IL6R and HMGB1 may serve as a new treatment for enzalutamide resistance in patients with advanced or metastatic prostate cancer. <i>Clin Cancer Res; 24(3); 708–23. ©2017 AACR</i>.</p></div>

With over 250,000 new cases annually, prostate cancer (PCa) is amongst the most diagnosed cancers in the United States. Despite a near-perfect 5-year survival rate in patients with localized disease with androgen deprivation therapy (ADT), about 10-20% of patients on ADT eventually develop castration-resistant prostate cancer (CRPC). Immunotherapies are typically ineffective in treating these treatment-resistant patients due to the abundance of immunosuppressive tumor-associated macrophages (TAMs) and lack of infiltrating lymphocytes. We propose to target these immunosuppressive macrophages through the triggering receptor expressed on myeloid cells 2 (TREM2), which has been identified as a major mediator of suppressive macrophage function but has not been studied in the context of PCa and CRPC. For this study, we analyzed publicly available RNA-seq datasets to query for TREM2 expression amongst patients with a range of prostate cancer disease states and cell types, measured tumor growth kinetics in two subcutaneous models of prostate cancer, and compared tumor immune infiltrates by flow cytometry. Our analysis of the TCGA prostate adenocarcinoma (PRAD) and the Stand Up to Cancer/Prostate Cancer Foundation (SU2C/PCF) datasets implicate TREM2 expression with prostate cancer progression, by Gleason score and progression-free status, and with worse overall survival of patients with metastatic CRPC (mCRPC). Manual curation and analysis of 10 single-cell RNA-seq datasets with a total of 84 patients, encompassing primary PCa, CRPC, and mCRPC indicate that TREM2 is highly and specifically expressed on TAMs in prostate cancer, with macrophages from patient-matched tumor samples expressing higher TREM2 compared to normal adjacent tissue. B6CaP tumors, with a luminal cytokeratin profile, high AR expression, and high Myc expression, show slower tumor growth in Trem2−/− mice compared to tumors in Trem2wt mice. On the other hand, RM1 tumors show no difference in growth kinetics on Trem2−/− mice. A major difference between the B6CaP and RM1 tumor microenvironments is the level of macrophage infiltration, where only 2-5% of immune cells in RM1 tumors are macrophages, compared to the 40-50% in B6CaP tumors. RM1 cells co-implanted with Trem2−/− macrophages show slower tumor growth, compared to tumor cells co-implanted with Trem2wt macrophages, confirming the role of Trem2-expressing macrophages in mediating tumor growth. Consistent with previous reports of suppressive Trem2 signaling, we also observed higher levels of inflammatory cytokine production in ex vivo stimulated Trem2−/− TAMs. By targeting TREM2 in prostate cancer, we find that TAMs are less suppressive, more inflammatory, and permit cytotoxic lymphocyte infiltration to enhance anti-tumor responses by synergizing with chemo and immune checkpoint therapy. Citation Format: Alex J. Lee, Kenneth Adusei, Monali Praharaj, Fan Shen, Xiaoxu Wang, Kaavya Bhatia, Thomas Nirschl, Jelani C. Zarif. Targeting immunosuppressive TREM2+tumor associated macrophages in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3923.

Androgen receptor (AR) is the primary oncogenic driver of prostate cancer, including aggressive castration-resistant prostate cancer (CRPC). The molecular mechanisms controlling AR activation in general and AR reactivation in CRPC remain elusive. Here we report that monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines, reciprocally interacts with AR in prostate cancer. MAOA was induced by androgens through direct AR binding to a novel intronic androgen response element of the MAOA gene, which in turn promoted AR transcriptional activity via upregulation of Shh/Gli-YAP1 signaling to enhance nuclear YAP1-AR interactions. Silencing MAOA suppressed AR-mediated prostate cancer development and growth, including CRPC, in mice. MAOA expression was elevated and positively associated with AR and YAP1 in human CRPC. Finally, genetic or pharmacologic targeting of MAOA enhanced the growth-inhibition efficacy of enzalutamide, darolutamide, and apalutamide in both androgen-dependent and CRPC cells. Collectively, these findings identify and characterize an MAOA-AR reciprocal regulatory circuit with coamplified effects in prostate cancer. Moreover, they suggest that cotargeting this complex may be a viable therapeutic strategy to treat prostate cancer and CRPC. SIGNIFICANCE: MAOA and AR comprise a positive feedback loop in androgen-dependent and CRPC, providing a mechanistic rationale for combining MAOA inhibition with AR-targeted therapies for prostate cancer treatment.

<div>Abstract<p>Androgen receptor (AR) is the primary oncogenic driver of prostate cancer, including aggressive castration-resistant prostate cancer (CRPC). The molecular mechanisms controlling AR activation in general and AR reactivation in CRPC remain elusive. Here we report that monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines, reciprocally interacts with AR in prostate cancer. MAOA was induced by androgens through direct AR binding to a novel intronic androgen response element of the <i>MAOA</i> gene, which in turn promoted AR transcriptional activity via upregulation of Shh/Gli-YAP1 signaling to enhance nuclear YAP1–AR interactions. Silencing MAOA suppressed AR-mediated prostate cancer development and growth, including CRPC, in mice. MAOA expression was elevated and positively associated with AR and YAP1 in human CRPC. Finally, genetic or pharmacologic targeting of MAOA enhanced the growth-inhibition efficacy of enzalutamide, darolutamide, and apalutamide in both androgen-dependent and CRPC cells. Collectively, these findings identify and characterize an MAOA–AR reciprocal regulatory circuit with coamplified effects in prostate cancer. Moreover, they suggest that cotargeting this complex may be a viable therapeutic strategy to treat prostate cancer and CRPC.</p>Significance:<p>MAOA and AR comprise a positive feedback loop in androgen-dependent and CRPC, providing a mechanistic rationale for combining MAOA inhibition with AR-targeted therapies for prostate cancer treatment.</p></div>

<div>Abstract<p>Androgen receptor (AR) is the primary oncogenic driver of prostate cancer, including aggressive castration-resistant prostate cancer (CRPC). The molecular mechanisms controlling AR activation in general and AR reactivation in CRPC remain elusive. Here we report that monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines, reciprocally interacts with AR in prostate cancer. MAOA was induced by androgens through direct AR binding to a novel intronic androgen response element of the <i>MAOA</i> gene, which in turn promoted AR transcriptional activity via upregulation of Shh/Gli-YAP1 signaling to enhance nuclear YAP1–AR interactions. Silencing MAOA suppressed AR-mediated prostate cancer development and growth, including CRPC, in mice. MAOA expression was elevated and positively associated with AR and YAP1 in human CRPC. Finally, genetic or pharmacologic targeting of MAOA enhanced the growth-inhibition efficacy of enzalutamide, darolutamide, and apalutamide in both androgen-dependent and CRPC cells. Collectively, these findings identify and characterize an MAOA–AR reciprocal regulatory circuit with coamplified effects in prostate cancer. Moreover, they suggest that cotargeting this complex may be a viable therapeutic strategy to treat prostate cancer and CRPC.</p>Significance:<p>MAOA and AR comprise a positive feedback loop in androgen-dependent and CRPC, providing a mechanistic rationale for combining MAOA inhibition with AR-targeted therapies for prostate cancer treatment.</p></div>

Background: Treatment-related neuroendocrine prostate cancer (NEPC) is an aggressive subset of castration-resistant prostate cancer (CRPC), found in ~20% of lethal CRPC. The mechanisms underlying the progression of prostate cancer to NEPC are largely unclear, and new drug targets are desperately needed. NEPC is known to be highly vascularized. Elevated expression of NE markers and increased angiogenesis are two prominent phenotypes of NEPC, and thus are expected to be linked. However, direct molecular links between these two phenotypes are still elusive, whose elucidation will substantially expand our knowledge in NEPC and enable the development of effective treatments for NEPC. Through RNAi & cDNA screening and functional validations, we previously discovered that GPCR-kinase 3 (GRK3) is essential preferentially for highly metastatic cancer cells as compared to lowly metastatic cancer cells. The mechanisms of GRK3 in prostate cancer progression were mostly unknown. Methods: We assessed GRK3’s expression in patient samples through IHC staining on TMA and data mining on public RNA-seq datasets with large cohorts. Using molecular and cell biology methods, we determined the impacts of GRK3 and HDAC2 overexpression and silencing on NE marker expression and angiogenesis in prostate cancer cells. Through biochemistry, we investigated the nature of GRK3-HDAC2 relation. By ChIP-PCR, we measured the impacts of GRK3 genetic and pharmacological modulations on HDAC2’s epigenetic activity. Through compound library screening and biochemical characterization, we searched for novel GRK3 inhibitors to study GRK3 biology and to evaluate whether GRK3 is a suitable drug target for prostate cancer. Results: GRK3 is significantly overexpressed in metastatic prostate tumors from patients, especially in NEPC. GRK3 promotes both angiogenesis and neuroendocrine differentiation in prostate cancer cells, indicating that it is a key missing link for these two phenotypes. Mechanistically, GRK3 enhances the epigenetic repressor activity of histone deacetylase 2 (HDAC2) to suppress key repressors of angiogenesis or NE phenotype. We have identified several compounds that block kinase activity of GRK3 much more potently than that of GRK2, the closest-related kinase to GRK3. Of note, our GRK3 inhibitors could substantially reduce angiogenesis and NE marker expression, as well as significantly inhibit NEPC cell growth in culture and in mouse xenografts. Conclusion: Kinase GRK3 connects angiogenesis and neuroendocrine differentiation in prostate cancer progression. Its mechanism of actions is at least in part through enhancing HDAC2’s epigenetic activity. Results based on our novel GRK3 inhibitors suggest that GRK3 is a valuable new drug target for aggressive prostate cancer. Citation Format: Samira Naderinezhad, Zheng Wang, Guoliang Zhang, Michael Ittmann, Martin Gleave, Wenliang Li. Kinase GRK3 connects angiogenesis and neuroendocrine differentiation in prostate cancer progression by enhancing epigenetic activity of HDAC2 [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A037.

Prostate stromal cells play a crucial role in the promotion of tumor growth and immune evasion in the tumor microenvironment (TME) through intricate molecular alterations in their interaction with prostate cancer (PCa) cells. While the impact of these cells on establishing an immunosuppressive response and influencing PCa aggressiveness remains incompletely understood. Our study shows that the activation of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) pathway in both prostate tumor and stromal cells, following androgen deprivation therapy (ADT), leads to the development of an immunosuppressive TME. Activation of LIF/LIFR signaling in PCa cells induces neuroendocrine differentiation (NED) and upregulates immune checkpoint expression. Inhibition of LIF/LIFR attenuates these effects, underscoring the crucial role of LIF/LIFR in linking NED to immunosuppression. Prostate stromal cells expressing LIFR contribute to NED and immunosuppressive marker abundance in PCa cells, while LIFR knockdown in prostate stromal cells reverses these effects. ADT‐driven LIF/LIFR signaling induces brain‐derived neurotrophic factor (BDNF) expression, which, in turn, promotes NED, aggressiveness, and immune evasion in PCa cells. Clinical analyses demonstrate elevated BDNF levels in metastatic castration‐resistant PCa (CRPC) and a positive correlation with programmed death‐ligand 1 (PDL1) and immunosuppressive signatures. This study shows that the crosstalk between PCa cells and prostate stromal cells enhances LIF/LIFR signaling, contributing to an immunosuppressive TME and NED in PCa cells through the upregulation of BDNF.