Mechanisms Of Immune Suppression Research Articles

Blockade of TIPE2-Mediated Ferroptosis of Myeloid-Derived Suppressor Cells Achieves the Full Potential of Combinatory Ferroptosis and Anti-PD-L1 Cancer Immunotherapy

Although immune checkpoint blockade (ICB) therapy has attained unprecedented clinical success, the tolerance and immune suppression mechanisms evolved by tumor cells and their tumor microenvironment (TME) hinder its maximum anti-cancer potential. Ferroptosis therapy can partially improve the efficacy of ICB, but it is still subject to immune suppression by myeloid-derived suppressor cells (MDSCs) in the TME. Recent research suggests that an MDSC blockade can unleash the full therapeutic potential of the combined therapy of ferroptosis and ICB in liver cancer treatment. However, whether blocking the intrinsic ferroptosis pathways of MDSCs can relieve imidazole ketone erastin (IKE)-initiated ferroptosis-induced immune suppression and ultimately trigger the optimal therapeutic effect of the combined ferroptosis and ICB therapy is still unknown. Here, we report that TIPE2, a phospholipid transfer protein, regulated the ferroptosis susceptibility in MDSCs through reprogramming lipid peroxidation-related phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species composition. TIPE2-deficient MDSCs resisted IKE-induced ferroptosis by up-regulating SLC7A11 and GPX4, and dissolved ferroptosis-induced immunosuppressive function by down-regulating lipid ROS whilst encouraging T cell proliferation and infiltration into tumor tissues to improve ferroptosis therapy. More importantly, TIPE2-deficient MDSCs achieved the full anti-tumor therapeutic potential of IKE-induced ferroptosis therapy and a PD-L1 blockade. These findings indicate that TIPE2 confers the ferroptosis sensitivity of MDSCs, and combining the targeting of the TIPE2 of MDSCs, ferroptosis therapy, and ICB is a novel therapeutic option for cancer treatment.

Induction of macrophage efferocytosis in pancreatic cancer via PI3Kγ inhibition and radiotherapy promotes tumour control

BackgroundThe immune suppression mechanisms in pancreatic ductal adenocarcinoma (PDAC) remain unknown, but preclinical studies have implicated macrophage-mediated immune tolerance. Hence, pathways that regulate macrophage phenotype are of strategic interest, with...

Immunohaemostasis and the significance of immune reactions in the regulation of blood coagulation.

This study was conducted to determine the specific features of the mutual influence of the immune and haemostatic systems in immunohaemostasis, the role of immune reactions in the regulationof blood coagulation, and the efficacy of modern methods of treating thrombosis andbleeding. The study analysed relevant scientific sources on immunology and haematology and identified the specific features of the blood clotting process and the role of immune reactions in it. The study found that the immune system influences the haematological system through the interaction of blood clotting factors, platelets, plasminogen, endothelial cells with immune cells. Thehaemostatic system influences the immune system through mechanisms to maintain immune tolerance and immune memory and the properties of clotting factors to activate the stimulation and migration of immune cells to the site of infection. Immune reactions regulate blood coagulation by activating platelets, regulating blood coagulation factors, affecting fibrinolysis, and immune tolerance. The process of platelet activation involves immune cells, immune complexes, and microbial components.The regulation of blood coagulation factors is influenced by the ability of immune cells to produce activators and inhibitors of these factors and to stimulate or slow down fibrinolysis. The immune system's maintenance of immune tolerance to blood components is regulated by mechanisms of immune response suppression, partial immune ignoring of certain blood elements, inhibition of activation of certain immune cells, apoptosis, and selection of immature T-lymphocytes. Treatment methods for patients at risk of thrombosis and bleeding include anticoagulation, antiplatelet, dual antiplatelet therapy, thrombectomy, endovascular methods, medical prophylaxis of bleeding, and coagulation monitoring. The findings of this study suggest the significance of immune responses in the regulation of blood coagulation processes, and therefore they can be used in the development of immunotherapy methods for the treatment of thrombosis and bleeding.

Multiomics reveals tumor microenvironment remodeling in locally advanced gastric and gastroesophageal junction cancer following neoadjuvant immunotherapy and chemotherapy

BackgroundPerioperative chemotherapy is the standard of care for patients with locally advanced gastric and gastroesophageal junction cancer. Recent evidence demonstrated the addition of programmed cell death protein 1 (PD-1) inhibitors...

Blocking WNT7A Enhances MHC-I Antigen Presentation and Enhances the Effectiveness of Immune Checkpoint Blockade Therapy.

The limited infiltration of CD8+ T cells in tumors hampers the effectiveness of T cell-based immunotherapy, yet the mechanisms that limit tumor infiltration by CD8+ T cells remain unclear. Through bulk RNA sequencing of human tumors, we identified a strong correlation between WNT7A expression and reduced CD8+ T-cell infiltration. Further investigation demonstrated that inhibiting WNT7A substantially enhanced MHC-I expression on tumor cells. Mechanistically, WNT7A inhibition inactivated Wnt/β-catenin signaling pathway and thus resulted in reduced physical interaction between β-catenin and p65 in the cytoplasm, which increased the nuclear translocation of p65 and activated the NF-κB pathway, ultimately promoting the transcription of genes encoding MHC-I molecules. We found that our lead compound, 1365-0109, disrupted the protein-protein interaction between WNT7A and its receptor FZD5, resulting in the upregulation of MHC-I expression. In murine tumor models, both genetic and pharmaceutical suppression of WNT7A led to increased MHC-I levels on tumor cells, and consequently enhanced the infiltration and functionality of CD8+ T cells, which bolstered antitumor immunity and improved the effectiveness of immune checkpoint blockade therapy. These findings have elucidated the intrinsic mechanisms of WNT7A-induced immune suppression, suggesting that therapeutic interventions targeting WNT7A hold promise for enhancing the efficacy of immunotherapy.

Bioinformatics analysis of the Microsporidia sp. MB genome: a malaria transmission-blocking symbiont of the Anopheles arabiensis mosquito

BackgroundThe use of microsporidia as a disease-transmission-blocking tool has garnered significant attention. Microsporidia sp. MB, known for its ability to block malaria development in mosquitoes, is an optimal candidate for supplementing malaria vector control methods. This symbiont, found in Anopheles mosquitoes, can be transmitted both vertically and horizontally with minimal effects on its mosquito host. Its genome, recently sequenced from An. arabiensis, comprises a compact 5.9 Mbp.ResultsHere, we analyze the Microsporidia sp. MB genome, highlighting its major genomic features, gene content, and protein function. The genome contains 2247 genes, predominantly encoding enzymes. Unlike other members of the Enterocytozoonida group, Microsporidia sp. MB has retained most of the genes in the glycolytic pathway. Genes involved in RNA interference (RNAi) were also identified, suggesting a mechanism for host immune suppression. Importantly, meiosis-related genes (MRG) were detected, indicating potential for sexual reproduction in this organism. Comparative analyses revealed similarities with its closest relative, Vittaforma corneae, despite key differences in host interactions.ConclusionThis study provides an in-depth analysis of the newly sequenced Microsporidia sp. MB genome, uncovering its unique adaptations for intracellular parasitism, including retention of essential metabolic pathways and RNAi machinery. The identification of MRGs suggests the possibility of sexual reproduction, offering insights into the symbiont’s evolutionary strategies. Establishing a reference genome for Microsporidia sp. MB sets the foundation for future studies on its role in malaria transmission dynamics and host-parasite interactions.

Obesity-Specific improvement of lung cancer outcomes and immunotherapy efficacy with metformin.

Pre-clinical cancer studies ascribe promising anticancer properties to metformin. Yet, clinical findings vary, casting uncertainty on its therapeutic value for non-small cell lung cancer (NSCLC) patients. We hypothesized that metformin could benefit obese and overweight patients with NSCLC. We retrospectively analyzed two clinical cohorts and employed complementary mouse models to test our hypothesis. One cohort included NSCLC patients with overweight BMI (≥25, n = 511) and non-overweight BMI (<25, n = 232) who underwent lobectomy, evaluating metformin's impact on clinical outcomes. Another cohort examined metformin's effect on progression-free survival (PFS) after immune checkpoint inhibitors (ICI) in overweight (n = 284) vs non-overweight (n = 184) NSCLC patients. Metformin's effects on tumor progression, antitumor immunity, and ICI response in obese and normal-weight mice were assessed with lung cancer models. Metformin is associated with increased recurrence-free survival in overweight patients (HR = 0.47 [95%CI = 0.24-0.94], p = .035) after lobectomy. It also corrected accelerated tumor growth in diet-induced obese mouse models in a lymphocyte-specific manner while reversing several mechanisms of immune suppression potentiated by obesity. PD-1 blockade coupled with metformin was more effective at limiting tumor burden in obese mice and correlated with PFS only in overweight patients on immunotherapy (HR = 0.60, [95%CI = 0.39-0.93], p = .024). Metformin may improve lung cancer-specific clinical outcomes in obese and overweight lung cancer patients and enhance immunotherapy efficacy in this growing population as well. This work identifies obesity as a potential predictive biomarker of metformin's anticancer and immunotherapy-enhancing properties in lung cancer while shedding light on the underlying immunological phenomena.

Differences in Plasma Extracellular Vesicles of Different Origin in On-Pump Versus Off-Pump Cardiac Surgery.

Coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB) causes a systemic inflammatory response that can worsen patient outcomes. Off-pump surgery has been associated with a reduced inflammatory response. The precise mechanisms and the role of extracellular vesicles (EVs) in this context are not fully understood. This study aimed to investigate the early immune response, including main T- and B-lymphocyte subsets, cytokine profiles, and plasma EVs, in patients undergoing off-pump (n = 18) and on-pump (n = 18) CABG. Thirty-six patients undergoing isolated CABG were enrolled in this randomized control study. Pre- and 24 h postoperative blood samples were analyzed for immune cell populations, cytokine levels, and plasma EV phenotyping. Off-pump CABG triggered a milder immune response than on-pump surgery. On-pump surgery led to greater changes in circulating EVs, particularly platelet- (CD62P+), endothelial- (CD31+), and B-cell-derived (CD19+), as well as platelet- and erythrocyte-derived aggregates (CD41+CD235a+). Levels of platelet-derived EVs, expressing both constitutional and activation markers (CD41+CD62P+) decreased in both groups of patients 24 h after surgery. On-pump cardiac procedures led to an increase in T-regulatory cell-derived EVs (CD73+CD39+), suggesting a potential mechanism for immune suppression compared to off-pump surgery. There were numerous correlations between EV levels and cytokine profiles following on-pump surgery, hinting at a close relationship. Leucocyte-derived EVs exhibited positive correlations with each other and with GRO but showed negative correlations with endothelial-derived EVs (CD90+ and CD31+). Additionally, CD73+ EVs demonstrated positive correlations with platelet counts and with erythrocyte-derived CD235a+ EVs. EV changes were significantly greater after on-pump surgery, highlighting a more pronounced response to this type of surgery and emphasizing the role of EVs as regulators of post-surgical inflammation.

Abstract C041: MYC and p53 alterations cooperate through VEGF signaling to repress cytotoxic T cell and immunotherapy responses in prostate cancer

Abstract Patients with castration-resistant prostate cancer (CRPC) are generally unresponsive to tumor targeted and immunotherapies. Whether genetic alterations acquired during the evolution of CRPC impact immune and immunotherapy responses is largely unknown. Using our innovative electroporation-based mouse models, we generated distinct genetic subtypes of CRPC found in patients and uncovered unique immune microenvironments. Specifically, mouse and human prostate tumors with MYC amplification and p53 disruption had weak cytotoxic lymphocyte infiltration and an overall dismal prognosis. MYC and p53 cooperated to induce tumor intrinsic secretion of VEGF, which by signaling through VEGFR2 expressed on CD8+ T cells, could directly inhibit T cell activity. Targeting VEGF-VEGFR2 signaling in vivo led to CD8+ T cell-mediated tumor and metastasis growth suppression and significantly increased overall survival in MYC and p53 altered CPRC. VEGFR2 blockade also led to induction of PD-L1, and in combination with PD-L1 immune checkpoint blockade produced anti-tumor efficacy in multiple preclinical CRPC mouse models. Thus, our results identify a genetic mechanism of immune suppression through VEGF signaling in prostate cancer that can be targeted to reactivate immune and immunotherapy responses in an aggressive subtype of CRPC. Citation Format: Katherine Murphy. MYC and p53 alterations cooperate through VEGF signaling to repress cytotoxic T cell and immunotherapy responses in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C041.

IMMU-35. TARGETING THE AHR IMMUNOMETABOLIC HUB DURING VIROIMMUNOTHERAPY OF GLIOMAS

Abstract Glioblastoma (GBM) poses a significant therapeutic challenge in oncology. Recent clinical trials have shown the feasibility of virotherapy to treat patients with GBM. Our laboratory developed an oncolytic adenovirus termed Delta-24-RGD that has been tested in clinical trials for recurrent GBM patients with encouraging results (NCT00805376, NCT02798406). These clinical studies, together with preclinical data, showed that the efficacy of Delta-24-RGD was due to direct tumor cell oncolysis and indirect activation of anti-tumor immune response. To further leverage this immune component, our group generated Delta-24-RGDOX, an armed version of Delta-24-RGD expressing the T-cell activator OX40-L, which exhibits a superior anti-cancer effect. In this project, we aim to further boost the effectiveness of Delta-24-RGDOX by targeting factors that maintain the immunosuppressive characteristic of gliomas. Specifically, we identified the environmental sensor and transcription factor Aryl Hydrocarbon Receptor (AhR) as one of the immunosuppressive factors. We show that AhR is overexpressed in GBM surgical specimens compared to healthy brain tissue, and high AhR expression correlates with poorer survival in glioma patients. Immunofluorescence staining of glioma cells treated with Delta-24-RGDOX demonstrated that AhR translocates to the nucleus, and qPCR showed that translocation resulted in the enhanced transcription of AhR-responsive elements. Additionally, bulk RNA-seq reveals that in vivo glioma models treated with Delta-24-RGDOX exhibit activation of the AhR pathway network. This unexpected and paradoxical activation may be responsible for immune suppression mechanisms, which might hinder the effect of Delta-24-RGDOX. Based on these data, we combined two innovative strategies, the oncolytic virus Delta-24-RGDOX and AhR inhibitors. Survival analysis in immunocompetent models of gliomas treated with this combined therapy showed the greatest therapeutic benefit compared to monotherapy controls. These findings highlight the critical role of AhR activation triggered by Delta-24-RGDOX and position AhR as a potential therapeutic target for enhancing the efficacy of oncolytic adenovirus therapy in GBM.

TMIC-49. TUMOR-DERIVED SPERMIDINE DRIVES IMMUNE SUPPRESSION IN THE GLIOBLASTOMA MICROENVIRONMENT VIA CD8 T CELL DEPLETION AND FUNCTIONAL ATTENUATION

Abstract A hallmark of glioblastoma (GBM) is an immunosuppressive microenvironment that is partially driven by tumor cell-derived secreted factors, highlighting the need for a more complete understanding of local immune suppressive mechanism. Altered secreted metabolite levels are observed in the GBM microenvironment; specifically, spermidine (a polyamine), which functions to drive cell proliferation, apoptosis, T cell lineage commitment, and myeloid cell-mediated suppression. However, the direct link between GBM cell-derived spermidine and the tumor microenvironment has yet to be determined. In syngeneic mouse GBM models, spermidine levels were increased in the tumor microenvironment and exogenous administration of spermidine accelerated tumor aggressiveness in an immune dependent-manner. Mechanistically, spermidine administration increased apoptosis of CD8+ T-cells and generated an exhausted phenotype. When ornithine decarboxylase (ODC1, the rate limiting enzyme in spermidine synthesis), was knocked down in tumor cells, no direct effect was observed on tumor cell growth. However, there was an increase in time to tumor succumbence and a concomitant increase in CD8+ T-cells and decrease in CD8+ T cell exhaustion. In GBM patients, there was a negative correlation between ODC1 expression and CD8+ T-cells present near the tumor. Additionally, patients with a favorable prognosis had significantly lower intratumoral levels of spermidine compared to patients with a poor prognosis. Taken together, these results demonstrate that spermidine functions as a tumor cell-derived metabolite that drives tumor progression through reducing CD8+T cell number and altering their phenotype. These findings have clinical implications as clinical trials using a polyamine biosynthesis inhibitor alone have not been very effective in GBM patients, suggesting the need for additional combination immunotherapies. Finally, spermidine is also produced at prominent levels by commensal gut microbes as well as absorbed from consumption of foods such as mushrooms; investigation into how these distal spermidine sources impact GBM growth via the gut-brain axis is actively ongoing.

Characterization of cell states in biliary tract cancers identifies mechanisms of therapeutic resistance in a phase II trial of DKN-01/nivolumab.

Biliary tract cancers demonstrate profound therapeutic resistance, and broadly effective therapies for refractory disease are lacking. We conducted a single-arm, second-line phase II trial combining DKN-01, a humanized monoclonal antibody targeting Dickkopf-1 (DKK-1), and nivolumab to treat patients with advanced biliary tract cancer (NCT04057365). No objective responses were seen. To identify mechanisms of treatment failure, we analyzed paired pre-treatment and on-treatment biopsies using scRNA-seq and constructed a detailed molecular classification of malignant and immune cells. We annotated five biliary tract cancer malignant cell states: classical, basal, mesenchymal, neural-like, and endothelial-like. Neural-like and endothelial-like states, which drive therapeutic resistance in other cancers, have not previously been described in BTC. Malignant cell states co-varied with distinct immune cell states, revealing diverse mechanisms of myeloid and T-cell mediated immune suppression, including M2 myeloid and terminally exhausted T cell programs that were induced by DKN-01/nivolumab. Here, we provide the first systematic classification of functionally annotated cell states in biliary tract cancer and provide new insight into resistance mechanisms to an immunotherapy combination that can inform the next generation of trials.

Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy

T cell inhibitory mechanisms prevent autoimmune reactions, while cancer immunotherapy aims to remove these inhibitory signals. Chronic ultraviolet (UV) exposure attenuates autoimmunity through promotion of poorly understood immune-suppressive mechanisms. Here we show that mice with subcutaneous melanoma are not responsive to anti-PD1 immunotherapy following chronic UV irradiation, given prior to tumor injection, due to the suppression of T cell killing ability in skin-draining lymph nodes. Using mass cytometry and single-cell RNA-sequencing analyzes, we discover that skin-specific, UV-induced suppression of T-cells killing activity is mediated by upregulation of a Ly6ahigh T-cell subpopulation. Independently of the UV effect, Ly6ahigh T cells are induced by chronic type-1 interferon in the tumor microenvironment. Treatment with an anti-Ly6a antibody enhances the anti-tumoral cytotoxic activity of T cells and reprograms their mitochondrial metabolism via the Erk/cMyc axis. Treatment with an anti-Ly6a antibody inhibits tumor growth in mice resistant to anti-PD1 therapy. Applying our findings in humans could lead to an immunotherapy treatment for patients with resistance to existing treatments.

Cortisol affects macrophage polarization by inducing miR-143/145 cluster to reprogram glucose metabolism and by promoting TCA cycle anaplerosis

Chronic stress can have adverse consequences on human health by disrupting the hormonal balance in our body. Earlier, we observed elevated levels of cortisol, a primary stress hormone, and some exosomal microRNAs in the serum of breast cancer patients. Here, we investigated the role of cortisol in microRNA induction and its functional consequences. We found that cortisol induced the expression of miR-143/145 cluster in human monocyte (THP1 and U937)-derived macrophages but not in breast cancer cells. In silico analysis identified glucocorticoid-response element in the upstream CARMN promoter utilized by the miR-143/145 cluster. Enhanced binding of glucocorticoid-receptor (GR) upon cortisol exposure and its regulatory significance was confirmed by chromatin-immunoprecipitation and promoter-reporter assays. Further, cortisol inhibited IFNγ-induced M1 polarization and promoted M2 polarization, and these effects were suppressed by miR-143-3p and miR-145-5p inhibitors pretreatment. Cortisol-treated macrophages exhibited increased oxygen-consumption rate (OCR) to extracellular-acidification rate (ECAR) ratio, and this change was neutralized by functional inhibition of miR-143-3p and miR-145-5p. HK2 and ADPGK were confirmed as the direct targets of miR-143-3p and miR-145-5p, respectively. Interestingly, silencing of HK2 and ADPGK inhibited IFNγ-induced M1 polarization, but failed to induce M2 polarization, since it suppressed both ECAR and OCR, while OCR was largely sustained in cortisol-treated M2-polarized macrophages. We found that cortisol treatment sustained OCR by enhancing fatty acid and glutamine metabolism through upregulation of CPT2 and GLS, respectively, to support M2 polarization. Thus, our findings unfold a novel mechanism of immune suppression by cortisol and open avenues for preventive and therapeutic interventions.

Dual A2A/A2B Adenosine Receptor Antagonist M1069 Counteracts Immunosuppressive Mechanisms of Adenosine and Reduces Tumor Growth In Vivo.

While A2A adenosine receptor (AR) was considered as a major contributor to adenosine-mediated immunosuppression, A2B, having the lowest affinity to adenosine, has also emerged as a potential contributor to tumor promotion. Therefore, in adenosine-rich tumor microenvironment (TME), where A2B could be complementary and/or compensatory to A2A, simultaneous targeting of A2A and A2B ARs can provide higher potential for cancer immunotherapy. We developed M1069-a highly selective dual antagonist of the A2A and A2B AR. In assays with primary human and murine immune cells, M1069 rescued IL2 production from T cells (A2A dependent) and inhibited VEGF production by myeloid cells (A2B dependent) in adenosine-high settings. M1069 also demonstrated superior suppression of the secretion of protumorigenic cytokines CXCL1, CXCL5, and rescue of IL12 secretion from adenosine-differentiated dendritic cells compared to an A2A-selective antagonist (A2Ai). In a one-way mixed lymphocyte reaction (MLR) assay, adenosine-differentiated human and murine dendritic cells treated with M1069 demonstrated superior T-cell stimulatory activity compared to dendritic cells differentiated in presence of A2Ai. In vivo, M1069 decreased tumor growth as a monotherapy and enhanced antitumor activity of bintrafusp alfa (BA) or cisplatin in syngeneic adenosinehi/CD73hi 4T1 breast tumor model, but not in the CD73 knockout 4T1 tumor model or in adenosinelow/CD73low MC38 murine colon carcinoma model. In summary, our dual A2A/A2B AR antagonist M1069 may counteract immune-suppressive mechanisms of high concentrations of adenosine in vitro and in vivo and enhance the antitumor activity of other agents, including BA and cisplatin.

Precision Targeting Strategies in Pancreatic Cancer: The Role of Tumor Microenvironment.

Pancreatic cancer demonstrates an ever-increasing incidence over the last years and represents one of the top causes of cancer-associated mortality. Cells of the tumor microenvironment (TME) interact with cancer cells in pancreatic ductal adenocarcinoma (PDAC) tumors to preserve cancer cells' metabolism, inhibit drug delivery, enhance immune suppression mechanisms and finally develop resistance to chemotherapy and immunotherapy. New strategies target TME genetic alterations and specific pathways in cell populations of the TME. Complex molecular interactions develop between PDAC cells and TME cell populations including cancer-associated fibroblasts, myeloid-derived suppressor cells, pancreatic stellate cells, tumor-associated macrophages, tumor-associated neutrophils, and regulatory T cells. In the present review, we aim to fully explore the molecular landscape of the pancreatic cancer TME cell populations and discuss current TME targeting strategies to provide thoughts for further research and preclinical testing.

Neratinib Alone or in Combination with Immune Checkpoint Inhibitors with or without Mammalian Target of Rapamycin Inhibitors in Patients with Fibrolamellar Carcinoma

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Fibrolamellar carcinoma (FLC) displays upregulation of several oncogenes, including &lt;i&gt;HER2&lt;/i&gt;, and multiple immune-suppressive mechanisms. We investigated the efficacy and safety of the pan-HER tyrosine kinase inhibitor neratinib as monotherapy (SUMMIT phase 2 basket study) or with immune checkpoint and/or mammalian target of rapamycin (mTOR) inhibitors (compassionate-use program) in patients with FLC. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Patients received neratinib 240 mg/day orally in SUMMIT, or as doublet or triplet combinations with pembrolizumab 2 mg/kg intravenously every 3 weeks, nivolumab 240 mg intravenously every 2 weeks, everolimus 7.5 mg/day orally, or sunitinib 37.5 mg/day orally under compassionate use. The primary endpoint in SUMMIT was objective response rate; safety was a secondary endpoint. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Fifteen patients with FLC received neratinib monotherapy in SUMMIT. The objective response rate was 5% (95% confidence interval [CI]: 0–21.8) and the disease control rate was 13.3% (95% CI: 1.7–40.5). Upon progression, five had added immune checkpoint inhibitors with or without everolimus or sunitinib. Two additional patients received neratinib-based combinations outside of SUMMIT, for a total of 17 neratinib-treated patients. One patient who received neratinib plus pembrolizumab had a confirmed partial response, one treated with neratinib plus everolimus had stable disease lasting 6 months, and one who received neratinib plus pembrolizumab plus sunitinib had stable disease lasting 16 months. Grade 3/4 adverse events with neratinib monotherapy occurred in 10 (66.7%)/2 (13.3%) patients, respectively. Grade 3 adverse events with neratinib-based combinations were hyperglycemia (&lt;i&gt;n&lt;/i&gt; = 1; neratinib plus pembrolizumab), hepatic failure, and anaphylaxis (&lt;i&gt;n&lt;/i&gt; = 1 each, neratinib plus pembrolizumab plus everolimus). There were no grade 4 adverse events with combination therapy. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; In patients with FLC, single-agent neratinib had limited efficacy, but clinical benefit was observed with neratinib in combination with immunotherapy and/or mTOR-targeted agents.

Targeting MDSC-HTR2B to Improve Immune Checkpoint Inhibitors in Breast to Brain Metastasis.

Myeloid Derived Suppressor Cells (MDSCs) support breast cancer growth via immune suppression and non-immunological mechanisms. Although 15% of patients with breast cancer will develop brain metastasis, there is scant understanding of MDSCs' contribution within the breast-to-brain metastatic microenvironment. Utilizing co-culture models mimicking a tumor-neuron-immune microenvironment and patient tissue arrays, we identified serotonergic receptor, HTR2B, on MDSCs to upregulate pNF-κB and suppress T cell proliferation, resulting in enhanced tumor growth. In vivo murine models of metastatic and intracranial breast tumors treated with FDA-approved, anti-psychotic HTR2B antagonist, clozapine, combined with immunotherapy anti-PD-1 demonstrated a significant increase in survival and increased T cell infiltration. Collectively, these findings reveal a previously unknown role of MDSC-HTR2B in breast-to-brain metastasis, suggesting a novel and immediate therapeutic approach using neurological drugs to treat patients with metastatic breast cancer.

Tumour Microenvironment: The General Principles of Pathogenesis and Implications in Diffuse Large B Cell Lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma worldwide, constituting around 30-40% of all cases. Almost 60% of patients develop relapse of refractory DLBCL. Among the reasons for the therapy failure, tumour microenvironment (TME) components could be involved, including tumour-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), tumour-associated neutrophils (TANs), cancer-associated fibroblasts (CAFs), and different subtypes of cytotoxic CD8+ cells and T regulatory cells, which show complex interactions with tumour cells. Understanding of the TME can provide new therapeutic options for patients with DLBCL and improve their prognosis and overall survival. This review provides essentials of the latest understanding of tumour microenvironment elements and discusses their role in tumour progression and immune suppression mechanisms which result in poor prognosis for patients with DLBCL. In addition, we point out important markers for the diagnostic purposes and highlight novel therapeutic targets.

PD-L1 regulates tumor proliferation and T-cell function in NF2-associated meningiomas.

Programmed death-ligand 1 (PD-L1) expression is an immune evasion mechanism that has been demonstrated in many tumors and is commonly associated with a poor prognosis. Over the years, anti-PD-L1 agents have gained attention as novel anticancer therapeutics that induce durable tumor regression in numerous malignancies. They may be a new treatment choice for neurofibromatosis type 2 (NF2) patients. The aims of this study were to detect the expression of PD-L1 in NF2-associated meningiomas, explore the effect of PD-L1 downregulation on tumor cell characteristics and T-cell functions, and investigate the possible pathways that regulate PD-L1 expression to further dissect the possible mechanism of immune suppression in NF2 tumors and to provide new treatment options for NF2 patients. PD-L1 is heterogeneously expressed in NF2-associated meningiomas. After PD-L1 knockdown in NF2-associated meningioma cells, tumor cell proliferation was significantly inhibited, and the apoptosis rate was elevated. When T cells were cocultured with siPD-L1-transfected NF2-associated meningioma cells, the expression of CD69 on both CD4+ and CD8+ T cells was partly reversed, and the capacity of CD8+ T cells to kill siPD-L1-transfected tumor cells was partly restored. Results also showed that the PI3K-AKT-mTOR pathway regulates PD-L1 expression, and the mTOR inhibitor rapamycin rapidly and persistently suppresses PD-L1 expression. Invivo experimental results suggested that anti-PD-L1 antibody may have a synergetic effect with the mTOR inhibitor in reducing tumor cell proliferation and that reduced PD-L1 expression could contribute to antitumor efficacy. Targeting PD-L1 could be helpful for restoring the function of tumor-infiltrating lymphocytes and inducing apoptosis to inhibit tumor proliferation in NF2-associated meningiomas. Dissecting the mechanisms of the PD-L1-driven tumorigenesis of NF2-associated meningioma will help to improve our understanding of the mechanisms underlying tumor progression and could facilitate further refinement of current therapies to improve the treatment of NF2 patients.