Prostate Cancer Immunotherapy Research Articles

Advances in Prostate Cancer Immunotherapy: Current Options and Emerging Novel Approaches

Prostate cancer (PCa) is a significant malignancy in men, contributing considerably to the rise in male mortality rates worldwide. Men diagnosed with PCa may have either localized or advanced stages of the disease. Globally, it ranks as the second most common and fifth most aggressive cancer type in males. The likelihood of developing prostate cancer in a man’s lifetime is approximately one in seven. Epidemiological research has linked various environmental and genetic factors to the abnormal growth of prostate cells, which leads to the formation of cancerous cells. Men experiencing a recurrence of prostate cancer or presenting with metastasis typically undergo androgen deprivation therapy (ADT), along with salvage radiotherapy and chemotherapy. While current treatment methods are more effective when used in combination, prostate cancer remains incurable. Research efforts are focused on exploring alternative treatments, including traditional medicine, nanotechnology applications, and gene therapy, to address drug resistance and mitigate the side effects associated with existing treatments. This article provides an overview the current treatment methods, and ongoing research into new treatment alternatives.

Inhibition of PIM kinase in tumor associated macrophages suppresses inflammasome activation and sensitizes prostate cancer to immunotherapy.

Immunotherapy has changed the treatment paradigm for many types of cancer, but immune checkpoint inhibitors (ICIs) have not shown benefit in prostate cancer (PCa). Chronic inflammation contributes to the immunosuppressive prostate tumor microenvironment (TME) and is associated with poor response to ICIs. The primary source of inflammatory cytokine production is the inflammasome. Here, we identify PIM kinases as important regulators of inflammasome activation in tumor associated macrophages (TAMs). Analysis of clinical data from a cohort of treatment naïve, hormone responsive PCa patients revealed that tumors from patients with high PIM1/2/3 display an immunosuppressive TME characterized by high inflammation (IL-1β and TNFα) and a high density of repressive immune cells, most notably TAMs. Strikingly, macrophage-specific knockout of PIM reduced tumor growth in syngeneic models of prostate cancer. Transcriptional analyses indicate that eliminating PIM from macrophages enhanced the adaptive immune response and increased cytotoxic immune cells. Combined treatment with PIM inhibitors and ICIs synergistically reduced tumor growth. Immune profiling revealed that PIM inhibitors sensitized PCa tumors to ICIs by increasing tumor suppressive TAMs and increasing the activation of cytotoxic T cells. Collectively, our data implicate macrophage PIM as a driver of inflammation that limits the potency of ICIs and provides preclinical evidence that PIM inhibitors are an effective strategy to improve the efficacy of immunotherapy in prostate cancer.

Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer

Unfolded protein response (UPR) is a central stress response pathway that is hijacked by tumor cells for their survival. Here, we find that IRE1α signaling, one of the canonical UPR arms, is increased in prostate cancer (PCa) patient tumors. Genetic or small molecule inhibition of IRE1α in syngeneic mouse PCa models and an orthotopic model decreases tumor growth. IRE1α ablation in cancer cells potentiates interferon responses and activates immune system related pathways in the tumor microenvironment (TME). Single-cell RNA-sequencing analysis reveals that targeting IRE1α in cancer cells reduces tumor-associated macrophage abundance. Consistently, the small molecule IRE1α inhibitor MKC8866, currently in clinical trials, reprograms the TME and enhances anti-PD-1 therapy. Our findings show that IRE1α signaling not only promotes cancer cell growth and survival but also interferes with anti-tumor immunity in the TME. Thus, targeting IRE1α can be a promising approach for improving anti-PD-1 immunotherapy in PCa.

Cell death score predicts prostate cancer metastasis and immunotherapy response.

Cell death score predicts prostate cancer metastasis and immunotherapy response.

Synergistic Potential of Nanomedicine in Prostate Cancer Immunotherapy: Breakthroughs and Prospects.

Given the global prevalence of prostate cancer in men, it is crucial to explore more effective treatment strategies. Recently, immunotherapy has emerged as a promising cancer treatment due to its unique mechanism of action and potential long-term effectiveness. However, its limited efficacy in prostate cancer has prompted renewed interest in developing strategies to improve immunotherapy outcomes. Nanomedicine offers a novel perspective on cancer treatment with its unique size effects and surface properties. By employing targeted delivery, controlled release, and enhanced immunogenicity, nanoparticles can be synergized with nanomedicine platforms to amplify the effectiveness of immunotherapy in treating prostate cancer. Simultaneously, nanotechnology can address the limitations of immunotherapy and the challenges of immune escape and tumor microenvironment regulation. Additionally, the synergistic effects of combining nanomedicine with other therapies offer promising clinical outcomes. Innovative applications of nanomedicine include smart nanocarriers, stimulus-responsive systems, and precision medicine approaches to overcome translational obstacles in prostate cancer immunotherapy. This review highlights the transformative potential of nanomedicine in enhancing prostate cancer immunotherapy and emphasizes the need for interdisciplinary collaboration to drive research and clinical applications forward.

NDR1 mediates PD-L1 deubiquitination to promote prostate cancer immune escape via USP10

Prostate cancer (PCa) is one of the most common male genitourinary system malignancies. Despite the significant benefits of anti-PD-L1 immune checkpoint inhibitor therapy in other cancers, the reasons for its poor therapeutic efficacy in prostate cancer (PCa) remain unclear.NDR1 plays an important role in innate immunity, but its role in tumor immunity and immunotherapy has not been investigated. The role of NDR1 in the immune microenvironment of PCa and the related mechanisms are unknown. Here, we found a positive correlation between NDR1 and PD-L1 expression in PCa. NDR1 significantly inhibits CD8 + T cell infiltration and function, thereby promoting immune escape in prostate cancer.More importantly, NDR1 inhibition significantly enhanced CD8 + T cell activation, which enhanced the therapeutic effect of anti-PD-L1. Mechanistic studies revealed that NDR1 inhibits ubiquitination-mediated PD-L1 degradation via the deubiquitinase USP10, upregulates PD-L1, and promotes PCa immune escape. Thus, our study suggests a unique PD-L1 regulatory mechanism underlying PCa immunotherapy failure. The significance of NDR1 in PCa immune escape and its mechanism of action were clarified, and combined NDR1/PD-L1 inhibition was suggested as an approach to boost PCa immunotherapy effectiveness.Graphical

Optimized Bionic Drug-Delivery-Inducing Immunogenic Cell Death and cGAS-STING Pathway Activation for Enhanced Photodynamic-Chemotherapy-Driven Immunotherapy in Prostate Cancer.

Prostate cancer presents as a challenging disease, as it is often characterized as an immunologically "cold" tumor, leading to suboptimal outcomes with current immunotherapeutic approaches in clinical settings. Photodynamic therapy (PDT) harnesses reactive oxygen species generated by photosensitizers (PSs) to disrupt the intracellular redox equilibrium. This process induces DNA damage in both the mitochondria and nucleus, activating the process of immunogenic cell death (ICD) and the cGAS-STING pathway. Ultimately, this cascade of events leads to the initiation of antitumor immune responses. Nevertheless, existing PSs face challenges, including suboptimal tumor targeting, aggregation-induced quenching, and insufficient oxygen levels in the tumor regions. To this end, a versatile bionic nanoplatform has been designed for the simultaneous delivery of the aggregation-induced emission PS TPAQ-Py-PF6 and paclitaxel (PTX). The cell membrane camouflage of the nanoplatform leads to its remarkable abilities in tumor targeting and cellular internalization. Upon laser irradiation, the utilization of TPAQ-Py-PF6 in conjunction with PTX showcases a notable and enhanced synergistic antitumor impact. Additionally, the nanoplatform has the capability of initiating the cGAS-STING pathway, leading to the generation of cytokines. The presence of damage-associated molecular patterns induced by ICD collaborates with these aforementioned cytokines lead to the recruitment and facilitation of dendritic cell maturation. Consequently, this elicits a systemic immune response against tumors. In summary, this promising strategy highlights the use of a multifunctional biomimetic nanoplatform, combining chemotherapy, PDT, and immunotherapy to enhance the effectiveness of antitumor treatment.

Characteristics, clinical significance, and cancer immune interactions of lipid metabolism in prostate cancer.

The relationship between lipid metabolism, immune response, and immunotherapy in prostate cancer (PCa) is closely intertwined, and targeted intervention in lipid metabolism may facilitate the success of anticancer immunotherapy. This research attempted to explore effective immunotherapy for PCa. We obtained RNA sequencing (RNA-seq) data for PCa patients from the UCSC Xena platform. Data analysis of differentially expressed genes (DEGs) was performed using package limma in R. Then, DEGs were subjected to enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The Human Protein Atlas (HPA) database was conducted to validate the protein expression of the up-regulated lipid metabolism related genes (LMRGs) between PCa tissues and normal prostate tissues. And then we identified critical transcription factors (TFs), LMRGs and miRNA by constructing a regulatory network of TF-gene-miRNA. Furthermore, we determined the high and low groups based on the score of lipid metabolism enrichment. The hallmark gene sets were derived from gene expression profiles using the gene set variation analysis (GSVA) R package. Finally, we conducted immune infiltration analysis and drug sensitivity analysis. Immune response and lipid metabolism have undergone significant changes in PCa and paracancerous tissues compared to normal tissues. A total of 21 LMRGs were differentially up-regulated in PCa. The TF-gene-miRNA network showed that PLA2G7, TWIST1, and TRIB3 may be the key genes that elevated lipid metabolism in PCa. The high group had more infiltration of B cell memory, macrophage M0, macrophage M1, and myeloid dendritic cell resting, and the low group had more infiltration of B cell plasma, monocyte, myeloid dendritic cell activated, and mast cell resting. The majority of checkpoint genes exhibited high expression levels in the low group. Lipid metabolism was remarkedly correlated with drug sensitivity. The analysis of lipid metabolism and related genes has revealed a complex regulatory mechanism that has a significant influence on immune response, immunotherapy, and medication guidance for patients with PCa. Prostate cancer (PCa); lipid metabolism; cancer immune; RNA sequencing (RNA-seq).

Identification of metastasis-related genes for predicting prostate cancer diagnosis, metastasis and immunotherapy drug candidates using machine learning approaches

BackgroundProstate cancer (PCa) is the second leading cause of tumor-related mortality in men. Metastasis from advanced tumors is the primary cause of death among patients. Identifying novel and effective biomarkers is essential for understanding the mechanisms of metastasis in PCa patients and developing successful interventions.MethodsUsing the GSE8511 and GSE27616 data sets, 21 metastasis-related genes were identified through the weighted gene co-expression network analysis (WGCNA) method. Subsequent functional analysis of these genes was conducted on the gene set cancer analysis (GSCA) website. Cluster analysis was utilized to explore the relationship between these genes, immune infiltration in PCa, and the efficacy of targeted drug IC50 scores. Machine learning algorithms were then employed to construct diagnostic and prognostic models, assessing their predictive accuracy. Additionally, multivariate COX regression analysis highlighted the significant role of POLD1 and examined its association with DNA methylation. Finally, molecular docking and immunohistochemistry experiments were carried out to assess the binding affinity of POLD1 to PCa drugs and its impact on PCa prognosis.ResultsThe study identified 21 metastasis-related genes using the WGCNA method, which were found to be associated with DNA damage, hormone AR activation, and inhibition of the RTK pathway. Cluster analysis confirmed a significant correlation between these genes and PCa metastasis, particularly in the context of immunotherapy and targeted therapy drugs. A diagnostic model combining multiple machine learning algorithms showed strong predictive capabilities for PCa diagnosis, while a transfer model using the LASSO algorithm also yielded promising results. POLD1 emerged as a key prognostic gene among the metastatic genes, showing associations with DNA methylation. Molecular docking experiments supported its high affinity with PCa-targeted drugs. Immunohistochemistry experiments further validated that increased POLD1 expression is linked to poor prognosis in PCa patients.ConclusionsThe developed diagnostic and metastasis models provide substantial value for patients with prostate cancer. The discovery of POLD1 as a novel biomarker related to prostate cancer metastasis offers a promising avenue for enhancing treatment of prostate cancer metastasis.

Improving cancer immunotherapy in prostate cancer by modulating T cell function through targeting the galectin-1.

Our study aimed to elucidate the role of Galectin-1 (Gal-1) role in the immunosuppressive tumor microenvironment (TME) of prostate cancer (PCa). Our previous findings demonstrated a correlation between elevated Gal-1 expression and advanced PCa stages. In this study, we also observed that Gal-1 is expressed around the tumor stroma and its expression level is associated with PCa progression. We identified that Gal-1 could be secreted by PCa cells, and secreted Gal-1 has the potential to induce T cell apoptosis. Gal-1 knockdown or inhibition of Gal-1 function by LLS30 suppresses T cell apoptosis resulting in increased intratumoral T cell infiltration. Importantly, LLS30 treatment significantly improved the antitumor efficacy of anti-PD-1 in vivo. Mechanistically, LLS30 binds to the carbohydrate recognition domain (CRD) of Gal-1, disrupting its binding to CD45 leading to the suppression of T cell apoptosis. In addition, RNA-seq analysis revealed a novel mechanism of action for LLS30, linking its tumor-intrinsic oncogenic effects to anti-tumor immunity. These findings suggested that tumor-derived Gal-1 contributes to the immunosuppressive TME in PCa by inducing apoptosis in effector T cells. Targeting Gal-1 with LLS30 may offer a strategy to enhance anti-tumor immunity and improve immunotherapy.

A Cu‐Based Single‐Atom Nanozyme Platform with Multi‐Enzyme Simulated Activities for Immunotherapy of Prostate Cancer by Regulating Cholesterol Metabolism and Triggering Pyroptosis

AbstractImmunotherapy, one of the most promising antitumor strategies, is used to treat prostate cancer (PCa). However, owing to the immunosuppressive tumor microenvironment (TME), the therapeutic effect of the antitumor immune response is greatly weakened. Therefore, there is an urgent need to explore new methods to enhance antitumor immune responses. In this study, a single‐atom nanozyme platform (Cu SA‐DOX@COD) that can trigger pyroptosis is developed to activate antitumor immune responses via a gasdermin E (GSDME)‐dependent pathway. It triggered pyroptosis by catalyzing the production of reactive oxygen species (ROS) and depleting reduced glutathione through intrinsic multi‐enzyme simulated activities and providing an oxygen source for cholesterol (CHOL) oxidation. Meanwhile, the loaded CHOL oxidase not only reduces the CHOL content of tumor cells to increase cell membrane permeability and inhibit tumor cell proliferation and invasion but also oxidizes CHOL and increases the level of H2O2 in tumor cells to enhance pyroptosis. In addition, the loaded doxorubicin activated caspase‐3 to cleave GSDME and further augment pyroptosis. Consequently, Cu SA‐DOX@COD enhances tumor cell immunocompetence and reshapes the immunosuppressive TME by triggering pyroptosis caused by a ROS storm, chemotherapy, and depleting CHOL, thereby activating systemic antitumor immunity to treat PCa.

The role of immunotherapy in urological cancers.

Immunotherapy is defined as a therapeutic approach that targets or manipulates the immune system. A deeper understanding of the cellular and molecular composition of the tumour environment, as well as the mechanisms controlling the immune system, has made possible the development and clinical investigation of many innovative cancer therapies. Historically, immunotherapy has played an essential role in treating urologic malignancies, while in the modern era, the development of immune checkpoint inhibitors (ICIs) has been critical to urology. Urothelial carcinoma is a common type of cancer in the genitourinary system, and treatment strategies in this area are constantly evolving. Intravesical and systemic immunotherapeutic agents have begun to be used increasingly frequently in treating urothelial carcinoma. These agents increase the anti-tumour response by affecting the body's defence mechanisms. Immunotherapeutic agents used in urothelial carcinoma include various options such as BCG, interferon, anti-PD-1 (pembrolizumab, nivolumab) and anti-PD-L1 (atezolizumab, avelumab, durvalumab). Renal cell carcinoma (RCC) has been known for many years as a tumour with unique sensitivity to immunotherapies. The recent emergence of ICIs that block PD-1/PD-L1 (pembrolizumab, nivolumab, atezolizumab) or CTLA4 (ipilimumab) signalling pathways has reestablished systemic immunotherapy as central to the treatment of advanced RCC. In light of randomized clinical trials conducted with increasing interest in the application of immunotherapies in the adjuvant setting, combination therapies (nivolumab/ipilimumab, nivolumab/cabozantinib, pembrolizumab/ axitinib, pembrolizumab/lenvantinib) have become the standard first-line treatment of metastatic RCC. Prostate cancer is in the immunologically "cold" tumour category; on the contrary, in recent years, immunotherapeutic agents have come to the fore as an essential area in the treatment of this disease. Especially in the treatment of castration-resistant prostate cancer, immunotherapeutic agents constitute an alternative treatment method besides androgen deprivation therapy and chemotherapy. Ipilimumab, nivolumab, pembrolizumab, atezolizumab, and Sipuleucel T (Vaccine-based) are promising alternative treatment options. Considering ongoing randomized clinical trials, immunotherapeutic agents promise to transform the uro-oncology field significantly. In this review, we aimed to summarize the role of immunotherapy in urothelial, renal and prostate cancer in the light of randomized clinical trials.

Recent Advances in Nanomaterial-Based Immunotherapy for Prostate Cancer: A Comprehensive Review

Abstract: Prostate Cancer (PCa) remains a global health concern, and recent advancements in nanomaterial- based immunotherapy are reshaping the landscape of its treatment. The advent of Prostate- Specific Antigen (PSA) screening had a significant impact on the PCa burden until the early 21st century, but the ongoing innovations in therapeutic approaches and early detection methods have contributed to a decline in mortality rates. This comprehensive review delves into the evolving role of the immune system in cancer, with a particular emphasis on the latest advances in nanomaterial- based immunotherapy for PCa. The review focuses on the burgeoning field of nanomaterial- based immunotherapy for PCa, particularly in the context of vaccine-based therapies and immune checkpoint inhibitors. Recent developments in clinical trials highlight the effectiveness of immune checkpoint inhibitors, such as CTLA-4 and PD-1 inhibitors, either as standalone treatments or in combination for metastatic Castration-Resistant Prostate Cancer (mCRPC). We highlight ongoing clinical trials that explore PSMA-targeted CAR-T cells for mCRPC patients, offering valuable insights into the promising field of nanomaterial-based immunotherapy. The review also discusses nanomaterial-based vaccine treatments, such as Sipuleucel-T (Provenge®) and G-VAX. These work in different ways to boost the immune system's response to Tumor-Associated Antigens (TAAs). We also explore viral vector-based vaccines and gene therapy approaches, highlighting their potential to enhance the immune system's ability to target prostate cancer cells at the nanoscale. The article concludes with an in-depth discussion of the current and emerging nanomaterial-based biomarkers for PCa diagnosis and prognosis.

IL-38 promotes the development of prostate cancer.

Prostate Cancer (PCa) remains a significant concern in male cancer-related mortality. Tumour development is intricately regulated by the complex interactions between tumour cells and their microenvironment, making it essential to determine which is/are key factor(s) that influence the progression of PCa within the tumour microenvironment. The current study utilised histopathology and immunohistochemistry to determine the expression of IL-38 in PCa and analysed the correlation between the expression level of IL-38 within PCa and clinical pathological characteristics. There was a significant increase in IL-38 expression in PCa tissues compared to adjacent non-PCa tissues (P < 0.0001). In addition, IL-38 expression was significantly higher in tumour cells with a high proliferation index compared to those with a low value-added index. ROC curve analysis demonstrated that IL-38 has high specificity and sensitivity for the diagnosis of PCa (AUC=0.76). Moreover, we Probed the cellular source of IL-38 in prostate cancer tissue by immunofluorescence double staining. Additionally, within PCa, the expression of IL-38 was inversely correlated with the expression levels of CD8 and PD-1. Survival analysis revealed a significantly lower overall survival rate for PCa patients with high IL-38 expression (P=0.0069), and when IL-38 was co-expressed with CD8, the survival rate of the IL-38high/CD8low group was decreased significantly. Multivariate analysis indicated that the expression level of IL-38 and TNM staging were independent predictors of survival in PCa patients. These findings suggest that IL-38 plays a crucial role in the development of PCa, and the exploration of the correlation between IL-38 and various immune factors in the tumour microenvironment further reveals its mechanism of action, making it a potential target for immunotherapy in PCa.

New approaches and prospects of immunotherapy and gene therapy for prostate cancer

Prostate cancer stands as the most prevalent cancer globally, constituting 21% of all cancer diagnoses in male patients. Urgent optimization of prostate cancer care is essential, given that this disease claims 345,000 lives every year. These innovative approaches hold substantial promise for both researchers and patients, representing a beacon of hope in the inhibitory act against prostate cancer. Prostate cancer's gradual advancement deems it suitable for immune therapy, but trials in metastatic cases show limited effectiveness, likely due to compromised immunity. Hindered by defective cellular responses, an immune-suppressive microenvironment, emerging evidence and breakthroughs, such as CAR-T therapy, inspire cautious optimism for advanced prostate cancer immunotherapy. Tumors utilize tactics to escape immune recognition, promoting the proliferation of MDSCs, Treg cells, and TAMs. Immunotherapy targets prostate cancer by mostly expressed target proteins and overexpressed target proteins. Immune cells play a role in tumor development and metastasis in advanced prostate cancer. Modulating the tumor microenvironment presents therapeutic possibilities. Certain prostate cancer types exhibit potential responses to immune checkpoint inhibitors, yet obstacles remain, necessitating additional research for enhanced efficacy. Immunotherapy faces hurdles in prostate cancer—limited inflammation, scarce antigens, and a resistant microenvironment. Grasping resistance intricacies is pivotal. The identification of DNA's helical structure propelled global progress in disease treatment through gene therapy. Choosing gene therapy vectors is critical; viruses are potent but toxic, while nonviral options, though less toxic, encounter barriers affecting transfection. In the realm of prostate cancer treatment, immunotherapy and gene therapy are emerging as increasingly viable options.

Combined therapy targeting AR and EZH2 curbs castration-resistant prostate cancer enhancing anti-tumor T-cell response.

Aim: Castration-resistant prostate cancer (CRPC) eventually becomes resistant to androgen receptor pathway inhibitors like enzalutamide. Immunotherapy also fails in CRPC. We propose a new approach to simultaneously revert enzalutamide resistance and rewire anti-tumor immunity. Methods: We investigated in vitro and in subcutaneous and spontaneous mouse models the effects of combining enzalutamide and GSK-126, a drug inhibiting the epigenetic modulator EZH2. Results: Enzalutamide and GSK-126 synergized to reduce CRPC growth, also restraining tumor neuroendocrine differentiation. The anti-tumor activity was lost in immunodeficient mice. Indeed, the combination treatment awoke cytotoxic activity and IFN-γ production of tumor-specific CD8+ T lymphocytes. Conclusion: These results promote the combination of enzalutamide and GSK-126 in CRPC, also offering new avenues for immunotherapy in prostate cancer.

Abstract 61: A novel immunotherapy for metastatic prostate cancer: A monoclonal antibody that can bind both STEAP1 and STEAP2

Abstract Prostate cancer (PCa) is the second most prevalent cancer among males, and the 5-year survival rate for patients with metastatic PCa (mPCa) is ~30%. Although significant progress has been made in improving survival in mPCa patients, many of these patients experience relapse or systemic toxicities. Protein expression of prostate-specific membrane antigen (PSMA), a common PCa antigen often targeted in PCa therapy, is unfortunately lost in the later stages of mPCa. In contrast, six transmembrane epithelial antigen of the prostate 1 and 2 (STEAP1 and STEAP2) are both overexpressed in most PCa compared to normal and vital organs and has emerged as a next-generation target in mPCa. We hypothesize that an antibody that binds to both STEAP1 and STEAP2 via their second extracellular domain (60% homology) could be useful therapeutically. Using an immunogen of this second extracellular domain, we raised several antibody clones that appear to have an affinity towards both STEAP1 and STEAP2 (STEAP1/2). The specificity and affinity of these antibody clones were successfully determined by immunofluorescence, flow cytometry and ELISA. Immunofluorescence results in PCa cell lines and those that overexpress STEAP1 and STEAP2 demonstrate the potential specificity of one clone for human STEAP1 and STEAP2. In addition, ELISA data revealed that the binding affinity of this clone to STEAP1 and STEAP2 is in the low nanomolar and low micromolar range, respectively. This monoclonal STEAP1/2 antibody has been sequenced and will become the basis for future development of immunotherapies thus expanding the therapeutic armamentarium for mPCa. Citation Format: Minzhi Sheng, Gobi Thillainadesan, Amanda Sparkes, Boyang Su, Esther Matus, Jessica Wright, Stanley Liu, Jean Gariepy, Hon S. Leong. A novel immunotherapy for metastatic prostate cancer: A monoclonal antibody that can bind both STEAP1 and STEAP2 [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 61.

Abstract 2639: Combined therapy targeting AR and EZH2 restrains the growth of castration resistant prostate cancer by enhancing antitumor T cell response

Abstract Castration resistant prostate cancer (CRPC) is a fatal disease. Androgen receptor pathway inhibitors, like enzalutamide, are initially effective but resistance eventually occurs, often associated to the emergence of aggressive neuroendocrine variants (NEPC). Even immunotherapy induced limited results in prostate cancer, governed by an immunosuppressive microenvironment. Therefore, effective therapies are needed. We here investigate in preclinical models a new approach aimed to revert castration resistance and simultaneously turn the immune milieu from “cold” to “hot”, through the combination between enzalutamide and the drug GSK-126, which inhibits the epigenetic modulator EZH2. We show that enzalutamide and GSK-126 can synergize to restrain the growth of CRPC in vitro and in vivo. Moreover, this therapeutic combination efficiently reduced NEPC differentiation, in both subcutaneous and autochthonous in vivo models, increasing the rate of cured mice with regressed lesions. The antitumor efficacy observed in immunocompetent mice bearing subcutaneous syngeneic CRPC tumors was lost in immunodeficient mice, indicating a contribution of immune cells. Additional experiments in the TRAMP spontaneous mouse model revealed that the combination of enzalutamide and GSK-126 significantly induced cytotoxic activity and IFNγ production by tumor-specific CD8+ T cells, otherwise tolerant, and increased IL-17 production by CD4+ T cells. The two drugs did not directly modulate T cell activity in vitro, suggesting the importance of microenvironment accomplices in triggering these effects. These results promote the combined use of enzalutamide and GSK-126 to restrain CRPC growth and NEPC differentiation, and, simultaneously, to awake antitumor T cell response, opening new possibilities for immunotherapy in prostate cancer. Citation Format: Irene Fischetti, Botti Laura, Roberta Sulsenti, Valeria Cancila, Claudia Enriquez, Renata Ferri, Marco Bregni, Filippo Crivelli, Claudio Tripodo, Mario P. Colombo, Elena Jachetti. Combined therapy targeting AR and EZH2 restrains the growth of castration resistant prostate cancer by enhancing antitumor T cell response [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 2639.

Abstract 5270: Androgen receptor blockade in macrophages primes NLRP3 inflammasome-mediated phagocytosis and tumor clearance in advanced prostate cancer

Abstract Immune-based therapies induce durable remissions in subsets of patients across multiple malignancies. However, there is limited efficacy of immunotherapy in metastatic castrate-resistant prostate cancer (mCRPC), manifested by an enrichment of immunosuppressive (M2) tumor-associated macrophages (TAM) in the tumor immune microenvironment (TME). Therefore, therapeutic strategies to overcome TAM-mediated immunosuppression are critically needed in mCRPC. Our single-cell RNA sequencing analysis in human tumors revealed that NLR family pyrin domain containing 3 (NLRP3), an innate immune sensing protein, is differentially expressed in TAM from metastatic PC patients treated with standard-of-care androgen deprivation therapy (ADT), relative to other tumor types and untreated primary PC. Furthermore, bulk RNA sequencing analysis in human mCRPC samples revealed an inverse relationship between NLRP3 expression and AR activity, with high NLRP3 expression associated with an M1 signature and a favorable clinical response to ICI in mCRPC. Based on these findings, we hypothesized that androgen axis blockade could enhance NLRP3 expression and potentiate innate immune tumor control in advanced PC. Critically, we discovered that blockade of TAM-intrinsic androgen receptor (AR) activity enhanced NLRP3 expression, but not inflammasome activity in the immunosuppressive (M2) TAM. In contrast, anti-tumor (M1) TAM exhibited high de novo NLRP3 expression, regardless of AR activity. The combination of AR blockade and NLRP3 agonism significantly enhanced phagocytosis of cancer cells by M2 TAM, whereas NLRP3 agonist treatment alone was sufficient to induce phagocytosis in M1 TAM. Following AR blockade/NLRP3 agonist combination treatment, all TAM acquired a distinct phenotype with high PD-L1 and CD86 expression, indicative of phagocytic TAM. Critically, NLRP3 agonism in combination with ADT resulted in significant tumor control in an aggressive c-myc driven advanced PC model, with 55% of mice achieving complete tumor clearance, which was abrogated by concurrent clodronate treatment (which systemically depletes phagocytic macrophages), thus demonstrating TAM-mediated phagocytosis enhancement as a major driver of the observed anti-tumor response. Collectively, our results identify NLRP3 as an AR-regulated “macrophage phagocytic checkpoint” that can be inducibly expressed and activated in TAM following ADT and NLRP3 agonist treatment, respectively, the combination resulting in TAM-mediated phagocytosis and tumor control. Citation Format: Kiranj Chaudagar, Srikrishnan Rameshbabu, Shenglin Mei, Taghreed Hirz, Ya-Mei Hu, Anna Argulian, Brian Labadie, Kunal Desai, Sam Grimaldo, Doga Kahramangil, Rishikesh Nair, Sabina DSouza, Dylan Zhou, Raymond Chen, Jordan Shafran, Mayme Loyd, Zheng Xia, David Sykes, Amy Moran, Akash Patnaik. Androgen receptor blockade in macrophages primes NLRP3 inflammasome-mediated phagocytosis and tumor clearance in advanced 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 5270.

Bilateral Choroidal Detachments following Novel CAR T-Cell Immunotherapy Regimen.

To describe a vision-threatening adverse event of a novel CAR T-cell immunotherapy for metastatic prostate cancer. Observational Case Report. 77-year-old male with history of metastatic prostate cancer and pulmonary embolism enrolled in a clinical trial investigating the use of CAR T-cell immunotherapy for treatment of metastatic prostate cancer presented with a subjective left temporal visual disturbance. The patient was found to have bilateral extensive choroidal detachments on examination. OCT macula demonstrated no intraretinal fluid or supraretinal fluid in both eyes. B-scan of both eyes redemonstrated choroidal detachments in both eyes and no retinal detachment in either eye. The patient was initiated on a topical and systemic steroid regimen and experienced symptomatic and clinical improvement. We exhibit a case of bilateral choroidal detachments secondary to systemic reaction to a novel immunotherapy for metastatic cancer successfully treated with systemic and topical steroids. Close follow up may be required for patients receiving similar novel immunotherapeutic regimens.