Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy.

Immune checkpoint therapy (ICT) shows encouraging results in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC) but still elicits a sub-optimal response among those with bone metastases. Analysis of patients' bone marrow samples revealed increased Th17 instead of Th1 subsets after ICT. To further evaluate the different tumor microenvironments, we injected mice with prostate tumor cells either subcutaneously or intraosseously. ICT in the subcutaneous CRPC model significantly increases intra-tumoral Th1 subsets and improves survival. However, ICT fails to elicit an anti-tumor response in the bone CRPC model despite an increase in the intra-tumoral CD4 T cells, which are polarized to Th17 rather than Th1 lineage. Mechanistically, tumors in the bone promote osteoclast-mediated bone resorption that releases TGF-ß, which restrains Th1 lineage development. Blocking TGF-ß along with ICT increases Th1 subsets and promotes clonal expansion of CD8 T cells and subsequent regression of bone CRPC and improves survival.

Prostate cancer-induced endothelial-cell-to-osteoblast transition drives immunosuppression in the bone-tumor microenvironment through Wnt pathway-induced M2 macrophage polarization.

Immune checkpoint therapy has limited efficacy for patients with bone-metastatic castration-resistant prostate cancer (bmCRPC). To improve immunotherapy for bmCRPC, we aimed to identify the mechanism of bmCRPC-induced changes in the immune microenvironment. Among bmCRPC patients, higher levels of a 32-gene M2-like macrophage signature in bone metastasis samples correlated with shorter overall survival. Immunohistochemistry showed that CD206-positive (CD206+) macrophages were enriched in bmCRPC bone biopsy specimens compared with primary tumors or lymph node metastases. In preclinical osteogenic prostate cancer (Pca) xenograft models, CD206+ macrophages were recruited to areas with tumor-induced bone. RNA sequencing (RNAseq) analysis showed higher expression of an M2-like gene signature, with activated canonical and noncanonical Wnt pathways, in tumor-associated macrophages isolated from osteogenic tumors (bone-TAMs) than in TAMs isolated from nonosteogenic tumors (ctrl-TAMs). Mechanistic studies showed that endothelial cells (ECs) that had undergone EC-to-osteoblast (EC-to-OSB) transition, the precursors of tumor-induced OSBs, produced paracrine factors, including Wnts, CXCL14, and lysyl oxidase, which induced M2 polarization and recruited M2-like TAMs to the bone-tumor microenvironment (bone-TME). Bone-TAMs suppressed CD8+ T cells' proliferation and cytolytic activity, and these effects were partially reversed by treating bone-TAMs with Wnt inhibitors. Genetic or pharmacological inhibition of Pca-induced EC-to-OSB transition reduced the levels of M2-like macrophages in osteogenic tumors. Our study demonstrates that Pca-induced EC-to-OSB transition drives immunosuppression in the bone-TME, suggesting that therapies that reduce Pca-induced bone formation may improve immunotherapeutic outcomes for bmCRPC.

The correlation between TRIM28 expression and immune checkpoints in CRPC.

This study delves into the unexplored realm of castration-resistant prostate cancer (CRPC) by investigating the role of TRIM28 and its intricate molecular mechanisms using high-throughput single-cell transcriptome sequencing and advanced bioinformatics analysis. Our comprehensive examination unveiled dynamic TRIM28 expression changes, particularly in immune cells such as macrophages and CD8+ T cells within CRPC. Correlation analyses with TCGA data highlighted the connection between TRIM28 and immune checkpoint expression and emphasized its pivotal influence on the quantity and functionality of immune cells. Using TRIM28 knockout mouse models, we identified differentially expressed genes and enriched pathways, unraveling the potential regulatory involvement of TRIM28 in the cGAS-STING pathway. In vitro, experiments further illuminated that TRIM28 knockout in prostate cancer cells induced a notable anti-tumor immune effect by inhibiting M2 macrophage polarization and enhancing CD8+ T cell activity. This impactful discovery was validated in an in situ transplant tumor model, where TRIM28 knockout exhibited a deceleration in tumor growth, reduced proportions of M2 macrophages, and enhanced infiltration of CD8+ T cells. In summary, this study elucidates the hitherto unknown anti-tumor immune role of TRIM28 in CRPC and unravels its potential regulatory mechanism via the cGAS-STING signaling pathway. These findings provide novel insights into the immune landscape of CRPC, offering promising directions for developing innovative therapeutic strategies.

Analysis of the immune-inflammatory indices for patients with metastatic hormone-sensitive and castration-resistant prostate cancer.

BACKGROUND: Inflammation plays a pivotal role in the progression of prostate cancer (PCa). Several immune-inflammatory indices, including neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), lymphocyte to monocyte ratio (LMR) and platelet to lymphocyte ratio (PLR), lung immune prognostic index (LIPI), systemic inflammation response index (SIRI) and systemic immune inflammation index (SII), have demonstrated their prognostic values in several solid malignancies. However, Comparisons of superiority with these seven indices' predictive efficacy within metastatic hormone-sensitive PCa (mHSPC) and metastatic castration-resistant PCa (mCRPC) remain uncertain. METHODS: We retrospectively included 407 patients diagnosed with mHSPC and 158 patients with mCRPC at West China Hospital from 2005 to 2022. The seven immune-inflammatory indices were computed based on hematological data of mHSPC at initial diagnosis and mCRPC at progression to CRPC. Prognostic value for castration-resistant prostate cancer-free survival (CFS), overall survival (OS), prostate-specific antigen progression-free survival (PSA-PFS) and prostate-specific antigen (PSA) response was assessed using Kaplan-Meier curves, Cox regression models, and chi-square tests. The predictive performance of each immune-inflammatory index was assessed using the area under the curve (AUC) in time-dependent receiver operating characteristic curve (ROC) analysis and C-index calculation. RESULTS: All seven immune-inflammatory indices were significantly associated with CFS and OS in the mHSPC cohort, as well as with PSA response, PSA-PFS, and OS in the mCRPC cohort. In the mHSPC cohort, LIPI consistently exhibited higher AUC values compared to NLR, dNLR, LMR, PLR, SII, and SIRI for predicting CFS and OS. This indicates that LIPI had a superior discriminative ability compared to the other indices (C-index of LIPI: 0.643 and 0.686 for CFS and OS, respectively). Notably, the predictive advantage of LIPI over other indices in the mHSPC stage diminished in the mCRPC stage. CONCLUSIONS: This study firstly confirmed the prognostic value of SII, SIRI and LIPI in mHSPC and mCRPC, and revealed that LIPI had a higher predictive power than NLR, dNLR, LMR, PLR, SII and SIRI in mHSPC. These non-invasive indices can enable clinicians to quickly assess the prognosis of patients.

Effective combinatorial immunotherapy for castration-resistant prostate cancer.

A significant fraction of patients with advanced prostate cancer treated with androgen deprivation therapy experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC). Immune checkpoint blockade using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types. However, mCRPC showed overwhelming de novo resistance to immune checkpoint blockade, motivating a search for targeted therapies that overcome this resistance. Myeloid-derived suppressor cells (MDSCs) are known to play important roles in tumour immune evasion. The abundance of circulating MDSCs correlates with prostate-specific antigen levels and metastasis in patients with prostate cancer. Mouse models of prostate cancer show that MDSCs (CD11b+Gr1+) promote tumour initiation and progression. These observations prompted us to hypothesize that robust immunotherapy responses in mCRPC may be elicited by the combined actions of immune checkpoint blockade agents together with targeted agents that neutralize MDSCs yet preserve T-cell function. Here we develop a novel chimaeric mouse model of mCRPC to efficiently test combination therapies in an autochthonous setting. Combination of anti-CTLA4 and anti-PD1 engendered only modest efficacy. Targeted therapy against mCRPC-infiltrating MDSCs, using multikinase inhibitors such as cabozantinib and BEZ235, also showed minimal anti-tumour activities. Strikingly, primary and metastatic CRPC showed robust synergistic responses when immune checkpoint blockade was combined with MDSC-targeted therapy. Mechanistically, combination therapy efficacy stemmed from the upregulation of interleukin-1 receptor antagonist and suppression of MDSC-promoting cytokines secreted by prostate cancer cells. These observations illuminate a clinical path hypothesis for combining immune checkpoint blockade with MDSC-targeted therapies in the treatment of mCRPC.

Prostate tumor RON receptor signaling mediates macrophage recruitment to drive androgen deprivation therapy resistance through Gas6-mediated Axl and RON signaling.

BACKGROUND: Androgen deprivation therapy (ADT), or chemical castration, is the first-line therapy for prostate cancer; however, resistance leaves few treatment options. Prostatic tumor-associated macrophages (TAMs) have been shown to promote prostate cancer growth and are abundant in castration-resistant prostate cancer (CRPC), suggesting a role in promoting CRPC. We recently showed a tumor cell-intrinsic mechanism by which RON promotes CRPC. Given previous reports that RON alters prostate cancer cell chemokine production and RON-overexpressing tumors alter macrophage function, we hypothesized that a macrophage-dependent mechanism regulated by tumor cell intrinsic RON also promotes CRPC. METHODS: Using RON-modulated genetically engineered mouse models (GEMMs) and GEMM-derived cell lines and co-cultures with bone marrow-derived macrophages, we show functional and molecular characteristics of signaling pathways in supporting CRPC. Further, we used an unbiased phosphokinase array to identify pathway interactions regulated by RON. Finally, using human prostate cancer cell lines and prostate cancer patient data sets, we show the relevance of our findings to human prostate cancer. RESULTS: Studies herein show that macrophages recruited into the prostate tumor microenvironment (TME) serve as a source for Gas6 secretion which serves to further enhance RON and Axl receptor activation in prostate tumor cells thereby driving CRPC. Further, we show targeting RON and macrophages in a murine model promotes CRPC sensitization to ADT. CONCLUSIONS: We discovered a novel role for the RON receptor in prostate cancer cells in promoting CRPC through the recruitment of macrophages into the prostate TME. Macrophage-targeting agents in combination with RON/Axl inhibition are likely to provide clinical benefits for patients with CRPC.

Improving power in PSA response analyses of metastatic castration-resistant prostate cancer trials.

BACKGROUND: To determine how much an augmented analysis approach could improve the efficiency of prostate-specific antigen (PSA) response analyses in clinical practice. PSA response rates are commonly used outcome measures in metastatic castration-resistant prostate cancer (mCRPC) trial reports. PSA response is evaluated by comparing continuous PSA data (e.g., change from baseline) to a threshold (e.g., 50% reduction). Consequently, information in the continuous data is discarded. Recent papers have proposed an augmented approach that retains the conventional response rate, but employs the continuous data to improve precision of estimation. METHODS: A literature review identified published prostate cancer trials that included a waterfall plot of continuous PSA data. This continuous data was extracted to enable the conventional and augmented approaches to be compared. RESULTS: Sixty-four articles, reporting results for 78 mCRPC treatment arms, were re-analysed. The median efficiency gain from using the augmented analysis, in terms of the implied increase to the sample size of the original study, was 103.2% (IQR [89.8,190.9%]). CONCLUSIONS: Augmented PSA response analysis requires no additional data to be collected and can be performed easily using available software. It improves precision of estimation to a degree that is equivalent to a substantial sample size increase. The implication of this work is that prostate cancer trials using PSA response as a primary endpoint could be delivered with fewer participants and, therefore, more rapidly with reduced cost.

Immunotherapeutic role of cabazitaxel treatment in the activation of TLR3 signalling in metastatic castration-resistant prostate cancer in vitro.

BACKGROUND: The activation of toll like receptors (TLR) potentially affect the inflammatory tumor microenvironment and thus is associated with tumor growth or inhibition. Cabazitaxel (CAB) has been effectively used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, the immune regulatory role of CAB in the tumor microenvironment is not clear. In this context, we for the first time assessed the immunotherapeutic role of CAB in the TLR3 signalling following activation of Poly I:C in mCRPC cells. METHODS AND RESULTS: The cytotoxic and apoptotic effects of CAB with the induction of Poly I:C were determined by WST-1, Annexin V, acridine orange, RT-PCR analysis, ELISA assay and immunofluorescence staining in DU-145 mCRPC and HUVEC control cells. Our findings showed that CAB treatment with Poly I:C significantly suppressed the proliferation of DU-145 cells through the induction of apoptosis and caspase activation. Additionally, higher concentration of CAB mediated the activation of TLR3 via increased cytoplasmic and nuclear expression of TLR3, TICAM-1 and IRF-3 in mCRPC cells. CONCLUSIONS: Co-treatment of CAB and Poly I:C was more effective in mCRPC cells with less toxicity in control cells. However, further investigations are required to elucidate the molecular mechanisms of TLRs signalling upon CAB treatment at the molecular level to further validate the immunotherapeutic efficacy of CAB in mCRPC.

Telomerase-based GX301 cancer vaccine in patients with metastatic castration-resistant prostate cancer: a randomized phase II trial.

Debate is around the optimal immunization regimen for cancer vaccines since too intense vaccination schedules may exhaust reactive lymphocytes. GX301 is a telomerase-based cancer vaccine whose safety and immunological effects were tested in a phase I trial applying an eight administrations schedule. Main objective of this study was to comparatively analyse safety and immunological response to three GX301 regimens in metastatic castration-resistant prostate cancer patients with response/disease stability after docetaxel chemotherapy. This was a multicentre, randomized, parallel-group, open-label trial registered with EudraCT (2014-000095-26) and ClinicalTrials.gov (NCT02293707, 2014). Ninety-eight patients were randomized to receive either eight (regimen 1), four (regimen 2) or two (regimen 3) vaccine administrations. Sixty-three patients were assessable for the primary immunological end-point. Vaccine-specific immune responses were evaluated by intracellular staining for IFN, elispot and cytotoxic assay at 90 and 180 days from baseline. No major side effects were recorded. A 54% overall immune responder rate was observed with 95% of patients showing at least one vaccine-specific immune response. Rate of immunological responders and number of immunizations were proportionally related, suggesting superiority of regimens 1 and 2 over regimen 3. Overall survival did not differ among regimens in both immunological responders and non-responders and was inversely associated (P = 0.002) with increase in the number of circulating CD8 + T regulatory cells at 180 days. These data indicate that GX301 cancer vaccine is safe and immunogenic in metastatic castration-resistant prostate cancer patients. Schedules with high number of administrations should be preferred in future studies due to their better immunological outcome.

Understanding the tumor-immune microenvironment in prostate cancer.

PURPOSE OF REVIEW: This review aims to highlight recent advances in prostate cancer tumor-immune microenvironment research and summarize the state-of-the-art knowledge of immune checkpoint inhibitors in prostate cancer. RECENT FINDINGS: Immune checkpoint inhibitors are the cornerstone of modern immunotherapy which have shown encouraging results across a spectrum of cancers. However, only limited survival benefit has been seen in patients with prostate cancer. Prostate cancer progression and its response to immunotherapies are strongly influenced by the tumor-immune microenvironment, whose feature can be summarized as low amounts of tumor-specific antigens, low frequency of tumor-infiltrating lymphocytes and high frequency of tumor-associated macrophages. To improve the therapeutic effect of immunotherapies, in recent years, many strategies have been applied, of which the most promising ones include the combination of multiple immunotherapeutic agents, the combination of an immunotherapeutic agent with other modalities in parallel or in sequential, and the development of biomarkers to find a subgroup of patients who may benefit the most from immunotherapeutic agents. SUMMARY: The impact of immune content and specific immune cell types on prostate cancer biology is highly complex. Recent clinical trials have shed light on the optimal use of immunotherapies for prostate cancer.

Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers.

Potent immunosuppressive mechanisms within the tumor microenvironment contribute to the resistance of aggressive human cancers to immune checkpoint blockade (ICB) therapy. One of the main mechanisms for myeloid-derived suppressor cells (MDSCs) to induce T cell tolerance is through secretion of reactive nitrogen species (RNS), which nitrates tyrosine residues in proteins involved in T cell function. However, so far very few nitrated proteins have been identified. Here, using a transgenic mouse model of prostate cancer and a syngeneic cell line model of lung cancer, we applied a nitroproteomic approach based on chemical derivation of 3-nitrotyrosine and identified that lymphocyte-specific protein tyrosine kinase (LCK), an initiating tyrosine kinase in the T cell receptor signaling cascade, is nitrated at Tyr394 by MDSCs. LCK nitration inhibits T cell activation, leading to reduced interleukin 2 (IL2) production and proliferation. In human T cells with defective endogenous LCK, wild type, but not nitrated LCK, rescues IL2 production. In the mouse model of castration-resistant prostate cancer (CRPC) by prostate-specific deletion of Pten, p53, and Smad4, CRPC is resistant to an ICB therapy composed of antiprogrammed cell death 1 (PD1) and anticytotoxic-T lymphocyte-associated protein 4 (CTLA4) antibodies. However, we showed that ICB elicits strong anti-CRPC efficacy when combined with an RNS neutralizing agent. Together, these data identify a previously unknown mechanism of T cell inactivation by MDSC-induced protein nitration and illuminate a clinical path hypothesis for combining ICB with RNS-reducing agents in the treatment of CRPC.

Intratumoral and s.c. injection of inactivated hemagglutinating virus of Japan envelope (GEN0101) in metastatic castration-resistant prostate cancer.

Inactivated hemagglutinating virus of Japan envelope (HVJ-E) has an antitumor effect and tumor immunity. We undertook an open-label, phase I, dose-escalation study in patients with castration-resistant prostate cancer (CRPC) to determine the safety and efficacy of intratumoral and s.c. injection of HVJ-E (GEN0101). Patients with CRPC, who were resistant to or unable to receive standard of care, were included. GEN0101 was injected directly into the prostate and s.c. in two 28-day treatment cycles. The primary end-points were to evaluate the safety and tolerability of GEN0101 and determine its recommended dose. The secondary end-points were to analyze the antitumor effect and tumor immunity. Three patients received 30 000 mNAU GEN0101 and 6 received 60 000 mNAU. There was no dose-limiting toxicity, and the recommended dose of GEN0101 was defined as 60 000 mNAU. Radiographically, 1 patient had stable disease and 2 had progressive disease in the low-dose group, whereas 5 patients had stable disease and 1 had progressive disease in the high-dose group. Three patients in the high-dose group showed reduction in lymph node metastasis. Prostate-specific antigen increase rates in the high-dose group were suppressed more than those in the low-dose group. Natural killer cell activity was enhanced in 2 patients of the low-dose group and in 5 patients in the high-dose group. In conclusion, intratumoral and s.c. injections of GEN0101 were well-tolerated and feasible to use. The study is registered with the UMIN Clinical Trials Registry (no. UMIN000017092).

Cancer-driven IgG promotes the development of prostate cancer though the SOX2-CIgG pathway.

BACKGROUND: Although androgen deprivation therapy (ADT) is the initial treatment strategy for prostate cancer (PCa), recurrent castration-resistant prostate cancer (CRPC) eventually ensues. In this study, cancer-derived immunoglobulin G (CIgG) is found to be induced after ADT, identifying CIgG as a potential CRPC driver gene. METHODS: The expression of CIgG and its clinical significance in PCa tissue was analyzed by The Cancer Genome Atlas database and immunohistochemistry. Subsequently, the sequence features of prostate cell line VHDJH rearrangements were analyzed. We also assessed the effect of CIgG on the migratory, invasive and proliferative abilities of PCa cells in vitro and vivo. Suspended microsphere, colony formation and drug-resistant assays were performed using PC3 cells with high CIgG expression (CIgGhigh ) and low CIgG expression (CIgG-/low ), and A nonobese diabetic/severe combined immunodeficiency mouse tumor xenograft model was developed for the study of the tumorigenic effects of the different cell populations. The SOX2-CIgG signaling pathway was validated by immunohistochemistry, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, Western blot, luciferase, and chromatin immunoprecipitation assays and bioinformatics analyses. Finally, we investigated the effect of RP215 inhibition on the progression of PCa in vivo using a Babl/c nude mouse xenograft model. RESULTS: CIgG is frequently expressed in PCa and associated with clinicopathological characteristics, moreover, CIgG transcripts with unique patterns of VHDJH rearrangements are found in PCa cells. Functional analyses identified that CIgG was induced by ADT and upregulated by SOX2 (SRY (sex determining region Y)-box 2) in PCa, promoting the development of PCa. In addition, our findings underscore a novel role of CIgG signaling in the maintenance of stemness and the progression of cancer through mitogen activated protein kinase/extracellular-signal-regulated kinase and AKT in PCa. In vivo experiments further demonstrated that depleting CIgG significantly suppressed the growth of PCa cell xenografts. Furthermore, a CIgG monoclonal antibody named RP215 exhibits tumor inhibitory effect as well. CONCLUSION: Our data suggests that CIgG could be a driver of PCa development, and that targeting the SOX2-CIgG axis may therefore inhibit PCa development after ADT.

Extreme responses to immune checkpoint blockade following bipolar androgen therapy and enzalutamide in patients with metastatic castration resistant prostate cancer.

BACKGROUND: Immune checkpoint inhibition has been shown to have limited efficacy in patients with metastatic prostate cancer. Prostate cancers that harbor certain homologous recombination (HR) DNA repair gene mutations, inactivating CDK12 mutations or have underlying mismatch repair deficiency may be effectively treated with immunotherapy. Combination therapy may improve clinical response rates to immune checkpoint blockade. We observed profound prostate-specific antigen (PSA) and/or objective responses to immune checkpoint blockade following prior treatment with bipolar androgen therapy (BAT) and enzalutamide. METHODS: We report three cases of patients with metastatic castration resistant prostate cancer (mCRPC) undergoing therapy with anti-PD-1 inhibitors. All patients underwent both somatic molecular testing and germline genetic testing. RESULTS: Two of the three patients with mCRPC harbored an inactivating mutation in an HR DNA repair gene (BRCA2, ATM). No patient demonstrated mismatch repair deficiency, nor were CDK12 alterations present. All three patients had been treated with BAT and enzalutamide before immune checkpoint blockade, a paradoxical approach for the treatment of mCRPC developed by our group. CONCLUSIONS: These cases of mCRPC suggest that immune checkpoint blockade may have therapeutic potential in patients with prostate cancer, especially following immune activation ("priming") using BAT and enzalutamide.

Determining the prognostic significance of IKKα in prostate cancer.

BACKGROUND: As the survival of castration-resistant prostate cancer (CRPC) remains poor, and the nuclear factor-κB (NF-κB) pathways play key roles in prostate cancer (PC) progression, several studies have focused on inhibiting the NF-κB pathway through generating inhibitory κB kinase subunit α (IKKα) small molecule inhibitors. However, the identification of prognostic markers able to discriminate which patients could benefit from IKKα inhibitors is urgently required. The present study investigated the prognostic value of IKKα, IKKα phosphorylated at serine 180 (p-IKKα S180) and threonine 23 (p-IKKα T23), and their relationship with the androgen receptor (AR) and Ki67 proliferation index to predict patient outcome. METHODS: A cohort of 115 patients with hormone-naïve PC (HNPC) and CRPC specimens available were used to assess tumor cell expression of proteins within both the cytoplasm and the nucleus by immunohistochemistry. The expression levels were dichotomized (low vs high) to determine the associations between IKKα, AR, Ki67, and patients'Isurvival. In addition, an analysis was performed to assess potential IKKα associations with clinicopathological and inflammatory features, and potential IKKα correlations with other cancer pathways essential for CRPC growth. RESULTS: High levels of cytoplasmic IKKα were associated with a higher cancer-specific survival in HNPC patients with low AR expression (hazards ratio [HR], 0.33; 95% confidence interval [CI] log-rank, 0.11-0.98; P = .04). Furthermore, nuclear IKKα (HR, 2.60; 95% CI, 1.27-5.33; P = .01) and cytoplasmic p-IKKα S180 (HR, 2.10; 95% CI, 1.17-3.76; P = .01) were associated with a lower time to death from recurrence in patients with CRPC. In addition, high IKKα expression was associated with high levels of T-cells (CD3+ P = .01 and CD8+ P = .03) in HNPC; however, under castration conditions, high IKKα expression was associated with high levels of CD68+ macrophages (P = .04), higher Gleason score (P = .01) and more prostate-specific antigen concentration (P = .03). Finally, we identified crosstalk between IKKα and members of the canonical NF-κB pathway in the nucleus of HNPC. Otherwise, IKKα phosphorylated by noncanonical NF-κB and Akt pathways correlated with members of the canonical NF-κB pathway in CRPC. CONCLUSION: The present study reports that patients with CRPC expressing high levels of nuclear IKKα or cytoplasmic p-IKKα S180, which associated with a lower time to death from recurrence, may benefit from IKKα inhibitors.

Docetaxel suppresses immunotherapy efficacy of natural killer cells toward castration-resistant prostate cancer cells via altering androgen receptor-lectin-like transcript 1 signals.

BACKGROUND: Docetaxel is an effective first-line chemotherapy agent used in the treatment of castration-resistant prostate cancer (CRPC) patients. However, most times chemotherapy with docetaxel eventually fails due to the development of docetaxel resistance. Natural killer (NK) cells are the first line of defense against cancer and infections. NK cell function is determined by a delicate balance between signals received via activating and inhibitory receptors. The aim of this study is to explore whether the potential docetaxel-resistant mechanism is associated with impaired NK cell cytotoxicity toward CRPC cells. METHODS: By performing MTT assay, we explored the role of docetaxel in regulating NK cells' cytotoxicity. Western blot and quantitative real-time polymerase chain reaction analysis were used to measure messenger RNA and protein levels separately. Luciferase reporter assay and chromatin immunoprecipitation assay were performed to analyze the mechanism. RESULTS: We found that docetaxel could suppress the immunotherapy efficacy of NK cells toward CRPC cells via the androgen receptor (AR)-lectin-like transcript 1 (LLT1) signals in vitro. Analysis of the mechanism revealed that docetaxel functioned through increasing AR to upregulate LLT1 expression in CRPC cells. AR transcriptionally activated LLT1 expression by binding to its promoter region. Furthermore, targeting AR with ASC-J9 or blocking LL1 by anti-human LLT1 monoclonal antibody could reverse the suppressive effect of docetaxel on the immunotherapy efficacy of NK cells toward CRPC cells. CONCLUSIONS: We concluded that chemotherapy agent docetaxel could increase AR that transcriptionally regulated the expression of NK inhibitory ligand LLT1 on CRPC cells. An increase of LL1 may further suppress the immunological efficacy of NK cells to kill CRPC cells. Additionally, targeting AR or blocking LL1 could enhance the immunotherapy efficacy of NK cells toward CRPC cells which might be considered as a new therapeutic option for the prevention or treatment of docetaxel resistance.

Mixed 20-peptide cancer vaccine in combination with docetaxel and dexamethasone for castration-resistant prostate cancer: a randomized phase II trial.

A novel cancer vaccine consisting of 20 mixed peptides (KRM-20) was designed to induce cytotoxic T lymphocytes (CTL) against twelve different tumor-associated antigens. The aim of this phase II trial was to examine whether KRM-20 in combination with docetaxel and dexamethasone enhances the antitumor effects in patients with castration-resistant prostate cancer (CRPC). In this double-blind, placebo-controlled, randomized phase II study, we enrolled chemotherapy-naïve patients with CRPC from ten medical centers in Japan. Eligible patients were randomly assigned 1:1 centrally to receive either KRM-20 combined with docetaxel and dexamethasone (n = 25) or placebo with docetaxel and dexamethasone (n = 26). The primary endpoint was the difference in prostate-specific antigen (PSA) decline between each treatment. The rates of > 50% PSA decline in the two arms were similar (56.5% versus 53.8%; P = 0.851). Human leukocyte antigen (HLA)-matched peptide-specific immunoglobulin G (P = 0.018) and CTL (P = 0.007) responses in the KRM-20 arm significantly increased after treatment. The addition of KRM-20 did not increase toxicity. There were no between-group differences in progression-free or overall survival (OS). The addition of KRM-20 was safe, and similar PSA decline and HLA-matched peptide-specific CTL and IgG responses increased in combination with docetaxel and dexamethasone in CRPC patients. Subgroup analysis suggested that this treatment is favorable for CRPC patients with ≥ 26% lymphocytes or PSA levels of < 11.2 ng/ml, but further clinical trials comparing OS are required.

Targeting defective DNA repair in prostate cancer.

PURPOSE OF REVIEW: Prostate cancer is the second leading cause of cancer death in men. Characterization of the genomic landscape of prostate cancer has demonstrated frequent aberrations in DNA repair pathways, identifiable in up to 25% patients with metastatic disease, which may sensitize to novel therapies, including PARP inhibitors and immunotherapy. Here, we summarize the current clinical landscape and future horizons for targeting defective DNA repair pathways in PC. RECENT FINDINGS: Several clinical trials have demonstrated efficacy of different PARP inhibitors in metastatic castration-resistant prostate cancer (mCRPC), most pronounced in those with BRCA mutations. The PROfound trial is the first positive phase 3 biomarker-selected trial to demonstrate improved outcomes with a targeted treatment, Olaparib, in mCRPC. Whilst the Keynote-199 trial failed to demonstrate efficacy of immune-checkpoint inhibitor pembrolizumab in unselected mCRPC patients, there was evidence of response in those harbouring DNA repair defects. SUMMARY: These landmark trials represent a significant advance towards personalization of PC therapy. However, resistance remains inevitable and there is a lack of reliable predictive biomarkers to select patients for treatment. Characterization of resistance mechanisms, and validation of novel biomarkers is critical to maximize clinical benefit and inform novel treatment combinations to improve outcomes.

Systematically understanding the immunity leading to CRPC progression.

Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second leading cause of cancer-related death in American men. Androgen deprivation therapy (ADT) has become a standard treatment strategy for advanced PCa. Although a majority of patients initially respond to ADT well, most of them will eventually develop castration-resistant PCa (CRPC). Previous studies suggest that ADT-induced changes in the immune microenvironment (mE) in PCa might be responsible for the failures of various therapies. However, the role of the immune system in CRPC development remains unclear. To systematically understand the immunity leading to CRPC progression and predict the optimal treatment strategy in silico, we developed a 3D Hybrid Multi-scale Model (HMSM), consisting of an ODE system and an agent-based model (ABM), to manipulate the tumor growth in a defined immune system. Based on our analysis, we revealed that the key factors (e.g. WNT5A, TRAIL, CSF1, etc.) mediated the activation of PC-Treg and PC-TAM interaction pathways, which induced the immunosuppression during CRPC progression. Our HMSM model also provided an optimal therapeutic strategy for improving the outcomes of PCa treatment.

The Open University's first one-day symposium on treatment-emergent neuroendocrine prostate cancer.

The Open University's first one-day symposium on treatment-emergent neuroendocrine prostate cancer attracted world-leading figures, early career researchers and industry colleagues. The symposium proved insightful into the 'real-world' impact and current problems faced in the diagnosis and treatment of neuroendocrine prostate cancer. It was important for this meeting to take place as the incidence of neuroendocrine prostate cancer is increasing due to the widespread use of next-generation androgen deprivation drugs. The symposium discussions proposed new molecularly driven deadlines to accelerate research and improved the treatment of this deadly and poorly recognized malignancy.