Suppressor Cell Research Articles

The Association between Systemic Inflammation and the Prostate Cancer: based on the National Health and Nutrition Examination Survey and Mendelian Randomization Analysis.

The purpose of this combination research was to examine the relationship between systemic inflammation and the risk of prostate cancer (PCa) through the National Health and Nutrition Examination Survey (NHANES) cross-sectional study and two-sample Mendelian randomization (MR) analysis. We incorporated NHANES data spanning the years 2001 to 2010, with exposure as systemic inflammation, evaluated using systemic immune-inflammation index (SII) and outcome as PCa, and performed multivariate logistic regression and restricted cubic spline (RCS) to test the correlation between SII and PCa. Further, two-sample MR was used to identify causal associations between specific immune cells and PCa. A total of 7706 participants (age≥40 years) were included in the analysis in the cross-sectional study, including 350 PCa cases, 7356 controls. Higher SII levels were associated with increased odds of PCa (P<.05). The odds ratio (OR) for PCa was 1.51 (95% CI 1.09-2.08) for the highest versus lowest quartile of SII levels in the fully adjusted model. Also, the RCS analysis showed a threshold effect, with SII levels above 8.90 associated with increased odds of PCa. In addition, MR results suggested a causal relationship between CD62L- monocyte, CD62L- HLA DR+ monocyte, CD14+ CD16+ monocyte, CD62L- Dendritic Cell, Monocytic Myeloid-Derived Suppressor Cell, CD28- CD8dim T cell, CD39+ resting CD4 regulatory T cell and PCa (P<.05). This combination analysis provides evidence for a significant causal relationship between systemic inflammation and PCa risk. These findings highlight systemic inflammation and inflammatory immune responses as potential modifiable risk factors for PCa.

IL-10RA governor the expression of IDO in the instruction of lymphocyte immunity.

Indoleamine 2,3-dioxygenase (IDO) impairs anti-pathogen and anti-tumour immunity. Mesenchymal stem cells (MSCs) modulate immunity via IDO but also suppress IFN-γ. While MSC IDO induction by IFN-γ is established, other drivers in this immunosuppressive setting remain unknown. Human bone marrow mesenchymal stem cells (MSCs) with IDO or IL-10RA knockdown were co-cultured with healthy donor T cells to assess immunosuppression. PDAC organoid anticancer activity was also tested in these co-cultures. Co-culturing MSCs with T cells in an IL-10RA-enriched environment enhances IDO expression, resulting in T cell suppression. Moreover, IL-10RA-positive MSCs collected from co-cultures with IL-10 supplementation show increased IDO expression. Conversely, MSCs with IL-10RA knockdown exhibit a significant reduction in IDO RNA and protein expression, as well as STAT3 phosphorylation status, which is a known upstream signalling pathway in IDO gene regulation, in T cell co-cultures. Down-regulation of IL-10RA also inhibits IDO activity in MSCs, resulting in reduced T cell suppression, and enabling the co-cultured T cells to kill PDAC organoids. Our research reveals IL-10RA as a pharmacological target in stromal cells for enhancing T cell-mediated PDAC eradication by downregulating IDO via blocked IL-10/IL-10RA signalling in MSCs. This advances IL-10RA interference in the tumour microenvironment (TME) to restore T cell cytotoxicity against cancers.

Etomoxir Sodium Salt Promotes Imidazole Ketone Erastin-Induced Myeloid-Derived Suppressor Cell Ferroptosis and Enhances Cancer Therapy.

Although ferroptosis inducers trigger ferroptotic tumor cells and immune cells in the tumor microenvironment (TME), imidazole ketone erastin (IKE)'s induction of ferroptosis shows no effect on tumor growth in immunocompetent tumor-bearing mice due to the presence of myeloid-derived suppressor cells (MDSCs). Treatment of the carnitine palmitoyltransferase 1a (CPT1A)-specific inhibitor decreases the immunosuppressive function of MDSCs and enhances ferroptotic inducer-initiated tumor cell ferroptosis. However, whether blocking CPT1A could enhance IKE-induced MDSC ferroptosis and thereby inhibit tumor growth is still unclear. Here, we report that a CPT1A-specific inhibitor, etomoxir sodium salt (Eto), and IKE combined treatment increased MDSC ferroptosis. Interestingly, the combination treatment of Eto and IKE blocked MDSCs' immunosuppressive function and accumulation by downregulating the expression of SLC7A11, GPX4, and ARG1 while promoting T-cell proliferation and infiltration into tumor tissues to enhance cancer therapy. These data provide a rationale for the combination therapy of a specific CPT1A inhibitor, Eto, with IKE in clinical settings.

Investigating disturbances of the core material system in the lung-gut axis of COPD based on the transcriptomics-metabolomics-microbiomics integration strategy

BackgroundAlthough still the significance of the lung-gut axis for COPD is increasingly highlighted, it’s urgent to ulteriorly comprehend the sophisticated disturbance of the core material system along the lung-gut axis, which is of great importance for the accurate precaution and prognosis of COPD efficiently. Aim of the studyThe purpose of this study was to analyze the information connections of the lung-gut axis, thus supporting the effective treatment of COPD. Materials and methodsAn integrated multi-omics approach was applied to explore the lung-gut axis in COPD rats. Firstly, based on transcriptomics, the ssGSEA algorithm was used to evaluate changes in pulmonary inflammatory cells. Then, the disturbances of metabolic pathways in lung and feces were revealed by the Lilikoi algorithm using LC-MS and 1H NMR metabolomics. Next, the composition and function of microbial communities in lung and feces were analyzed by 16 s rRNA sequencing. Finally, the association analysis was employed to explore the possible crosstalk between the lung and gut. Furthermore, the core material system in the lung-gut axis was described based on network topology analysis. ResultFirstly, 1652 differential expression genes (involving in immune response-regulating signaling pathway, etc.) and 15 types of inflammatory cells (including neutrophil, etc.) were identified related to COPD. 135 pulmonary differential metabolites (involving in arachidonic acid metabolism, etc.) and 105 fecal differential metabolites (involving in alanine metabolism, etc.) were revealed by metabolomics. The f_Pasteurellaceae, etc. and g_Ruminococcus_2, etc. were identified associated with COPD in lung and gut. Finally, disturbances of the core material system, composed of macrophage, neutrophil, activated dendritic cell, myeloid derived suppressor cell, arachidonic acid metabolism, alpha linolenic acid & linoleic acid metabolism, g_Psychrobacter in lung and bile secretion, p_Proteobacteria in gut, were obtained to analyze the possible information flow of the lung-gut axis. ConclusionThe core material system for the lung-gut axis have been revealed, which might contribute to the illustration of the pathogenesis of COPD. In the future, more researches are required on the impact of the core material system in the lung-gut axis on the onset and recovery process of COPD, suggesting more precise identifying effective treatments for the disease.

Single cell and spatial transcriptomics highlight the interaction of club-like cells with immunosuppressive myeloid cells in prostate cancer

Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prostate TME at multiple points in the standard treatment timeline employing single-cell RNA-sequencing and spatial transcriptomics data from 120 patients. We identify club-like cells as a key epithelial cell subtype that acts as an interface between the prostate and the immune system. Tissue areas enriched with club-like cells have depleted androgen signaling and upregulated expression of luminal progenitor cell markers. Club-like cells display a senescence-associated secretory phenotype and their presence is linked to increased polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) activity. Our results indicate that club-like cells are associated with myeloid inflammation previously linked to androgen deprivation therapy resistance, providing a rationale for their therapeutic targeting.

Effect of External Beam Radiation Therapy and Brachytherapy on Circulating Myeloid-Derived Suppressor Cell Populations in Patients Treated Definitively for Cervical Cancer

PurposeThe immunosuppressive function of myeloid derived suppressor cells (MDSCs) has been implicated in the regulation of immune responses against cancer and is associated with poor prognosis. Radiation treatment is known to alter immune cell populations within the tumor, however, whether this results in recruitment of immunosuppressive MDSC populations is not well understood. Here we evaluate the response of circulating MDSC populations in patients treated per standard of care cisplatin chemoradiation therapy (CRT) for locally invasive cervical cancer. Methods and MaterialsNewly diagnosed, treatment naïve patients with locally advanced cervical cancer were enrolled. Blood samples were collected from patients prior to starting CRT (T0), after external beam radiation therapy (EBRT) (T1), and after high-dose rate brachytherapy (T2). Samples from each timepoint were processed and prevalence of MDSC subsets were determined by flow cytometry. MDSC populations were identified by Live/Dead-CD11b+CD33+HLA-DR- staining. MDSC subsets were further subdivided into granulocytic (g-, CD15+CD14-), monocytic (m-, CD15-CD14+), or early-MDSCs (e-, CD15-CD14-). ResultsMost patients in our study were Caucasian non-smokers with HPV-associated squamous cell carcinoma of the cervix. We saw a trend for increased MDSC frequency in patients with more advanced stage disease at the time of initiating treatment. MDSCs increase in response to CRT and peak after brachytherapy (T2). In particular, the g-MDSC subset which increases 6.44x relative to baseline. There was no correlation between MDSC expansion and response to therapy. ConclusionOur study confirms other reports that circulating MDSCs in patients with cervical cancer increase in response to CRT and are associated with more advanced stage. Additionally, we show that MDSC expansion is driven by the g-MDSC subset. We did not see any correlation between MDSC expansion and treatment response, though this may be due to the limited sample size for this study

Abstract 4138661: Targeting Arginase I Alleviates Cardiomyopathy

Introduction: Emerging data have shown that pathological cardiac fibrosis and heart failure is driven by recruitment of CD4 + T cells to injured heart tissue. Systemic deletion of CD4 + T cells or splenectomy has been shown to attenuate CD4 + T cell heart infiltration and inflammation. We engineered cargo-less nanoparticles using a biocompatible and biodegradable polymer that target splenic macrophages to overexpress arginase I, leading to local depletion of L-arginine, an amino acid crucial for CD4 + T cell activation and expansion. Hypothesis: Cargo-less nanoparticles attenuate CD4 + T cell activation, expansion, and heart infiltration in experimental models of cardiomyopathy by regulating cross talk between macrophages and CD4 + T cells via L-arginine depletion in the spleen. Methods: Spleen-targeting, cargo-less nanoparticles were synthesized from poly(L-lactide-co-glycolide) (PLLGA) and administered to murine and human macrophages in vitro. Arginase I expression and activity were assessed via Western blotting and arginase activity assay. Epigenetic modulation was analyzed using Western blotting and CHIP-seq. Conditioned media was collected to culture CFSE-labeled T cells to assess proliferation. The nanoparticles were administered to mouse heart failure models induced by isoproterenol or angiotensin II and phenylephrine. Immune cell composition in mouse spleens and hearts was investigated by flow cytometry. Cardiac function was assessed by echocardiography and heart fibrosis was examined via immunohistochemistry and Western blotting. Results: Primary murine macrophages treated with our nanoparticles exhibited a dose-dependent T cell suppression in vitro. This effect was abrogated when an arginase inhibitor was administered together with the nanoparticles. The nanoparticles upregulated arginase I protein expression and arginase activity by increasing histone lactylation. In vivo testing with mouse heart injury models showed that the nanoparticles restored levels of effector and regulatory T cells in injured mice to non-injured levels. Additionally, the nanoparticles reduced cardiac fibrosis and restored ejection fraction. Furthermore, Western blotting of heart tissue lysate revealed that the nanoparticles downregulated the TGFb and p-SMAD signaling pathway. Conclusion: Collectively, these findings highlight a novel therapeutic strategy for heart failure, addressing the gap of fibrosis treatment by targeting upstream immunological pathways.

IMMU-64. SEX-SPECIFIC ROLES OFYAP1 AND CD276/B7-H3 IN MEDULLOBLASTOMA IMMUNE SUPPRESSION

Abstract The molecular mechanism governing sex disparities in cancer prevalence, progression, and treatment outcomes represents an important yet understudied area of research with significant implications for cancer treatment. Medulloblastoma (MB), the most prevalent pediatric brain malignancy, exhibits a notable sex bias in incidence and survival rates. Males have a higher incidence rate across all age groups and have worse prognoses than their females for age groups over three years old. Here, we report an unanticipated sex-biased role of the oncogene Yap1 in SHH medulloblastoma. Our results reveal that Yap1 deletion significantly prolongs survival in male, but not female mice with SmoM2-driven SHH MB. Employing an integrated multi-omics approach, we demonstrate that YAP1 is required to maintain cancer stem cells simultaneously activating stemness genes (such as Sox2) and repressing differentiation genes (such as Neurod1 and Zic1/2) in both sexes. In contrast, Yap1 plays a more critical role in immune evasion in males than in females. Specifically, YAP1 regulates the expression of the immune checkpoint molecule Cd276/B7-H3, which suppresses cytotoxic T cell function. In males, CD276 blockade or Yap1 deletion in MB cells is enough to reverse T cell suppression effectively. In females, neither CD276 blockade nor Yap1 deletion alone in MB cells can reverse T cell suppression. Furthermore, YAP1’s direct transcriptional target gene signatures, including CD276, predict survival across multiple human cancers in male patients. These findings suggest broader implications of our findings beyond medulloblastoma and indicate a highly conserved mechanism across species. Our study provides compelling evidence for the male-biased efficacy of Yap1 or CD276 inhibitors and presents novel insights into sex-specific mechanisms of cancer immune evasion.

Targeting squalene epoxidase restores anti-PD-1 efficacy in metabolic dysfunction-associated steatohepatitis-induced hepatocellular carcinoma

ObjectiveSqualene epoxidase (SQLE) promotes metabolic dysfunction-associated steatohepatitis-associated hepatocellular carcinoma (MASH-HCC), but its role in modulating the tumour immune microenvironment in MASH-HCC remains unclear.DesignWe established hepatocyte-specific Sqle transgenic (tg) and knockout...

IMMU-04. G-AMINOBUTYRIC ACID DRIVES GLIOBLASTOMA IN FEMALES IN AN IMMUNE-DEPENDENT MANNER

Abstract Communication with a neuronal network and accumulation of myeloid-derived suppressive cells (MDSCs) support GBM growth and therapeutic resistance. GBM incidence and outcomes differ between males and females. We previously demonstrated that granulocytic (gMDSCs) drive GBM in females. However, a lack of understanding of the host factors regulating distinct MDSC subset function remains to be a major obstacle for therapeutically targeting these cells in GBM. In this study, we identified γ-aminobutyric acid (GABA) pathway as a modulator of gMDSC activity. gMDSCs from both healthy adults and glioma patients, expressed significantly higher levels of GABA receptor B1 (GABBR1) and GABA receptor B2 (GABBR2) compared to monocytic MDSCs (mMDSCs). On contrary, GABA receptor A (GABAAR) subunits were not expressed in either MDSC subtype. Given these differences, we investigated the effect of GABA on MDSC metabolism and found an increase in L-arginine metabolism specifically in female gMDSCs following GABA treatment while no significant metabolic changes were observed in any other groups. In MDSCs, L-arginine can be metabolized via nitric oxide synthase (NOS2) or Arginase-1 (Arg-1). While treatment with GABA or the GABBR agonist baclofen increased NOS2 production in specifically in female gMDSCs, Arg-1 was not affected. Mechanistically, baclofen enhanced gMDSC-mediated T cell suppression in females. In preclinical models of GBM, baclofen treatment resulted in a truncated survival only in immunocompetent female mice, which was reversed by pharmaceutical inhibition of NOS2. Clinically, female patients on GABA analogs (pregabalin, gabapentin) had significantly lower 12-month survival probabilities compared to control population. This effect was not observed in male patients. Conversely, inhibition of GABBR with CGP35348 prolonged survival in female GBM models and reprogramed the immunosuppressive tumor microenvironment. Collectively, these results highlight that GABA alters anti-tumor immune response in a sex-specific manner. These results support the future assessment of GABA pathway inhibitors as potential immunotherapy agents in GBM.

Mediating role of circulating inflammatory proteins in the effect of immune cells on esophageal cancer risk: A Mendelian randomization study.

The immune system and inflammatory processes play crucial roles in the development of esophageal cancer (EC). This study aimed to investigate the causal relationships between 731 immune cell phenotypes, 91 circulating inflammatory proteins, and EC, with a particular focus on the mediating role of circulating inflammatory proteins. Utilizing public genetic data, we applied a 2-sample Mendelian Randomization (MR) method to examine the causal relationships between 731 immune cell phenotypes, 91 circulating inflammatory proteins, and EC. Comprehensive sensitivity analyses were conducted to assess the robustness, heterogeneity, and horizontal pleiotropy of the MR results. Additionally, a 2-step MR method was employed to quantify the impact and proportion of immune cell phenotypes mediated by circulating inflammatory proteins on EC. Eleven immune cell phenotypes and 1 inflammatory cytokine were found to have causal relationships with EC, with results stable across all sensitivity analyses. Mediation analyses revealed that only 2 cell phenotypes had causal relationships with EC through interleukin-10: CD3 on human leukocyte antigen-DR (HLA-DR)+ T cells (mediation effect = -0.009; mediation proportion = 12.01%) and monocytic myeloid-derived suppressor cell absolute count (mediation effect = 0.018; mediation proportion = 18.97%). This study enhances the understanding of the causal relationships between immune cells, circulating inflammatory proteins, and EC. The findings highlight the potential mediating role of interleukin-10, providing new insights into the mechanisms by which immune cells may influence esophageal tumorigenesis.

METTL14-mediated m6A modification upregulated SOCS3 expression alleviates thyroid cancer progression by regulating the JAK2/STAT3 pathway

Thyroid cancer (TC) is the most common malignant tumor of the head and neck. As a common epigenetic modification in mRNAs, N6-methyladenosine (m6A) modification plays critical roles in biological process of cancers. However, m6A methyltransferase methyltransferase-like 14 (METTL14)-mediated m6A modification and its potential regulatory mechanisms in TC are not fully elucidated. In our study, we observed that METTL14 was decreased in TC tissues and cells. And upregulation of METTL14 induced apoptotic cell death and hampered cell proliferation, epithelial mesenchymal transition (EMT) and tumor growth in vitro and in vivo. Mechanistically, METTL14 increased the expression of suppressor of cytokine signaling 3 (SOCS3) through m6A methylation modification, and knockdown of SOCS3 reversed the inhibitory effect of overexpressing METTL14 on TC tumorigenesis. In addition, METTL14-mediated m6A modification of SOCS3 inactivated the janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway, and in the METTL14-overexpressing TC cells, silencing SOCS3-induced upregulation of cell proliferation, EMT and suppression of apoptosis was reversed by JAK2/STAT3 inhibitor AG490 and WP1066. Together, we indicated that METTL14/m6A/SOCS3/JAK2/STAT3 axis play an important role in the progression of TC.

Novel 1,8-Naphthalimide Derivatives Inhibit Growth and Induce Apoptosis in Human Glioblastoma.

Given the rapid advancement of functional 1,8-Naphthalimide derivatives in anticancer research, we synthesized these two novel naphthalimide derivatives with diverse substituents and investigated the effect on glioblastoma multiforme (GBM) cells. Cytotoxicity, apoptosis, cell cycle, topoisomerase II and Western blotting assays were evaluated for these compounds against GBM in vitro. A human GBM xenograft mouse model established by subcutaneously injecting U87-MG cells and the treatment responses were assessed. Both compounds 3 and 4 exhibited significant antiproliferative activities, inducing apoptosis and cell death. Only compound 3 notably induced G2/M phase cell cycle arrest in the U87-MG GBM cells. Both compounds inhibited DNA topoisomerase II activity, resulting in DNA damage. The in vivo antiproliferative potential of compound 3 was further validated in a U87-MG GBM xenograft mouse model, without any discernible loss of body weight or kidney toxicity noted. This study presents novel findings demonstrating that 1,8-Naphthalimide derivatives exhibited significant GBM cell suppression in vitro and in vivo without causing adverse effects on body weight or kidney function. Further experiments, including investigations into mechanisms and pathways, as well as preclinical studies on the pharmacokinetics and pharmacodynamics, may be instrumental to the development of a new anti-GBM compound.

Current advancements in PD-L1 modulation by CMTM6 in malignant tumors

Abstract The CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6), a member of the chemokine-like factor superfamily, binds to programmed death-ligand 1 (PD-L1) on the cell membrane, thereby impeding PD-L1’s lysosomal degradation and sustaining its expression. In recent years, extensive studies on PD-L1 have provided insights into its function as an immunepoint inhibitor involved in tumor cell immune evasion. The specific interaction between CMTM6 and PD-L1 suggests a potential role in tumor cell immune evasion and suppression, potentially offering a novel therapeutic target for cancer immunotherapy. Currently, the research on CMTM6 and PD-L1 in diverse tumors and diseases is limited, but their significant roles are indicated. This article provides an overview of the impact of CMTM6 on the immune microenvironment in different types of cancer (such as lung cancer, breast cancer, and liver cancer), and summarizes the effects of CMTM6 on the occurrence and development of various tumors.

Sinomenine hydrochloride alleviates autoimmune myocarditis via suppressing Th1 cell induced-M1 macrophage pyroptosis

Abstract Background Myocarditis is typical of the complex inflammatory response in the heart with high morbidity and mortality, accompanied by tissue damage and cardiac fibrosis. Previous studies have demonstrated that CD4+ T cells are crucial to the cardiac autoimmunity of myocarditis, but the role of different CD4+ T cell subsets remains unclear. Recently, sinomenine hydrochloride, a natural compound from the traditional Chinese herb Sinomenium acutum, is reported to inhibit T cell proliferation in some systemic autoimmune diseases such as rheumatoid arthritis. Given that autoimmune myocarditis is an organ-specific autoimmune disease, the effect of sinomenine hydrochloride on autoimmune myocarditis demands further study. Purpose This study aims to elucidate the role of CD4+ T-helper 1 (Th1) cells in regulating inflammatory cell death in autoimmune myocarditis and investigate the pharmacological effect of sinomenine hydrochloride on CD4+ Th1 cells and autoimmune myocarditis. Methods Male Balb/c mice were immunized with myosin heavy chain-α peptides to establish the experimental autoimmune myocarditis (EAM) model, followed by the treatments with sinomenine hydrochloride by gavage. Tohoku Hospital Pediatrics-1 (THP-1) cell line and murine T cells were used for in vitro experiments. Results In the acute phase of EAM, we observed plenty of CD4+ T cells infiltrating the heart tissue. RNA sequencing revealed that among the genes encoding typical transcription factors of CD4+ T cell subset, only Tbx21 and Stat4, both representing Th1 cells, were upregulated, which consisted with immunofluorescence staining. Further studies indicated that Th1 cells not only mediated classical activated macrophage (M1 macrophage) polarization by secreting interferon-γ (IFN-γ) but also associated with pro-inflammatory macrophage pyroptosis in the EAM, with the cleavage of gasdermin D (GSDMD), caspase-1 and IL-1β. Subsequent in vitro experiments confirmed that IFN-γ could dramatically promote macrophage pyroptosis combined with ATP, leading to the release of IL-1β and IL-18(Figure 1). To find an effective method for Th1 cell suppression and myocarditis remission, we identified that sinomenine hydrochloride impeded Th1 cell activation, differentiation and proliferation in vitro. Furthermore, sinomenine hydrochloride inhibited Th1 cell infiltration and M1 macrophage pyroptosis in the EAM heart, In the chronic phase, cardiac remodeling and fibrosis were suppressed, and cardiac systolic function was significantly improved in the treatment group (Figure 2). Conclusion Our study demonstrates that Th1 cells-induced M1 macrophage pyroptosis is an essential pathogenic mechanism of EAM. Sinomenine hydrochloride can alleviate the severity and progression of EAM, which may become a novel therapeutic strategy for treating myocarditis.Figure 1Figure 2

Reduced T and NK Cell Activity in Glioblastoma Patients Correlates with TIM-3 and BAT3 Dysregulation.

Inhibitory receptors are critical for regulating immune cell function. In cancer, these receptors are often over-expressed on the cell surface of T and NK cells, leading to reduced anti-tumor activity. Here, through the analysis of 11 commonly studied checkpoint and inhibitory receptors, we discern that only HAVCR2 (TIM3) and ENTPD1 (CD39) display significantly greater gene expression in glioblastoma compared to normal brain and lower grade glioma. Cell surface TIM-3, but not ENTPD1, was also elevated on activated CD4+ and CD8+ T cells, as well as on NK cells from glioblastoma patients compared to healthy donor T and NK cells. A subsequent analysis of molecules known to co-ordinate TIM-3 function and regulation was performed, which revealed that BAT3 expression was significantly reduced in CD4+ and CD8+ T cells, as well as NK cells from glioblastoma patients compared to counterparts from healthy donors. These pro-inhibitory changes are also correlated with reduced levels of the activation marker CD69 and the pro-inflammatory cytokine IFNγ in CD4+ and CD8+ T cells, as well as NK cells from glioblastoma patients. Collectively, these data reveal that glioblastoma-mediated CD4+ and CD8+ T cell and NK cell suppression is due, at least in part, to dysregulated TIM-3 and BAT3 expression and the associated downstream immunoregulatory and dysfunctional effects.

Amplifying glioblastoma immunotherapy: T cell shielding through Nitric oxide/reactive oxygen species scavenging nanoparticles Potentiates anti-PD-1

Despite the success of immune checkpoint blockade (ICB) therapy in various cancers, its efficacy faces challenges in glioblastoma (GBM) due to the immunosuppressive cold-tumor microenvironment. The scarcity of tumor-infiltrating T cells and the suppression of T cell activity significantly limit therapeutic outcomes in GBM. Nitric oxide (NO) and reactive oxygen species (ROS) from tumor-associated myeloid cells (TAMCs) are key contributors to T cell suppression, reducing ICB therapy effectiveness. In this study, we developed NO-ROS scavenging micelles that effectively scavenge both NO and ROS, protecting T cells from their exhausting effects. This leads to a significant increase in T cell infiltration and activation. Moreover, when combined with αPD-1, the survival rate increases to 40 % up to 120 days, enhancing therapeutic efficacy compared to αPD-1 alone. This approach not only protects T cells from the inhibitory effects of NO and ROS but also has the potential to reshape the tumor microenvironment, overcoming T cell suppression in cold tumors.

The Level of Circulating M-MDSCs as an Indicator for the Therapeutic Outcome of BNCT in End-Stage Malignant Brain Tumor Patients

PurposeBoron neutron capture therapy (BNCT) is a promising treatment modality for patients diagnosed with malignant brain tumors. It is currently used for emergency and compassionate purposes to treat end-stage malignant glioma or recurrent head and neck cancer patients in Taiwan. Understanding the factors influencing treatment response is crucial for optimizing patient care. This study aimed to investigate the association between tumor response and various parameters in end-stage malignant glioma patients following BNCT. Patients and MethodsFifteen patients with end-stage malignant brain tumors underwent a single fraction of BNCT. The treatment response was evaluated using cranial magnetic resonance imaging, and the association between treatment response and BNCT parameters was analyzed. Additionally, circulating myeloid-derived suppressor cell (MDSC) levels were measured by flow cytometry and correlated with patients’ survival. ResultsBNCT exhibited significant therapeutic efficacy in reducing tumor volume of these end-stage glioma patients, with 3 patients achieving complete response and 10 patients achieving partial response within 1 month, resulting in an impressive objective response rate of 80%. The median overall survival is 9 (1.77, 12.47) months, and the progression-free survival is 1.34 (0.53, 9.53) months. Kaplan-Meier analysis showed that the patients with complete response and partial response displayed better survival than those with stable disease. Treatment response was not significantly associated with initial tumor size, blood boron concentration, tumor-to-normal tissue ratio, or tumor-to-blood ratio. The ROC curve revealed a cut-off value of 5% of circulating M-MDSCs with a sensitivity of 66.67% and specificity of 73.33%, respectively, for predicting the glioma patient’s response to BNCT. ConclusionThis clinical study demonstrates that BNCT can reduce tumor burden, improve disease control, and prolong survival in end-stage glioma patients. Circulating M-MDSCs may serve as a predictive indicator for the treatment response of these patients following BNCT.

Precise Preparation of Supramolecular Spherical Nucleic Acids for Nucleolin-Targeted Gene Delivery.

Molecular spherical nucleic acids (m-SNAs) are a second generation of spherical nucleic acids (SNAs), which are of significance in potential application of targeted delivery of nucleic acids or gene regulation due to their defined molecular structures. Nevertheless, m-SNAs typically involve a single DNA sequence which greatly limits its functions as either targeting purpose or gene regulation. In response, we proposed here a third generation, supramolecular spherical nucleic acids (Supra-SNAs) with two different sequences to achieve both above-mentioned functions. Specifically, we constructed a series of supramolecular self-assembly structures by coupling a cell membrane receptor (i.e., nucleolin)-recognizing aptamer (AS1411)-modified adamantine as targeting probe and human epithelial growth factor receptor 2 (HER2) antisense-functionalized β-cyclodextrin to specifically inhibit the overexpression of HER2 proteins for gene regulations. In comparison to the m-SNA precursors, such Supra-SNA structures exhibited enhanced levels of resistance to nuclease degradation, cellular uptake, gene regulation capabilities and tumor retention capacity. We demonstrated that Supra-SNAs exhibited optimal cell suppression rates and cell apoptosis via a phosphatidylinositol 3-kinase/protein kinase B signaling pathway. The well-defined molecular structures provide an attractive platform for investigating interrelationship between structure and property at the molecular level.

Precise Preparation of Supramolecular Spherical Nucleic Acids for Nucleolin‐Targeted Gene Delivery

AbstractMolecular spherical nucleic acids (m‐SNAs) are a second generation of spherical nucleic acids (SNAs), which are of significance in potential application of targeted delivery of nucleic acids or gene regulation due to their defined molecular structures. Nevertheless, m‐SNAs typically involve a single DNA sequence which greatly limits its functions as either targeting purpose or gene regulation. In response, we proposed here a third generation, supramolecular spherical nucleic acids (Supra‐SNAs) with two different sequences to achieve both above‐mentioned functions. Specifically, we constructed a series of supramolecular self‐assembly structures by coupling a cell membrane receptor (i.e., nucleolin)‐recognizing aptamer (AS1411)‐modified adamantine as targeting probe and human epithelial growth factor receptor 2 (HER2) antisense‐functionalized β‐cyclodextrin to specifically inhibit the overexpression of HER2 proteins for gene regulations. In comparison to the m‐SNA precursors, such Supra‐SNA structures exhibited enhanced levels of resistance to nuclease degradation, cellular uptake, gene regulation capabilities and tumor retention capacity. We demonstrated that Supra‐SNAs exhibited optimal cell suppression rates and cell apoptosis via a phosphatidylinositol 3‐kinase/protein kinase B signaling pathway. The well‐defined molecular structures provide an attractive platform for investigating interrelationship between structure and property at the molecular level.