B7-H3 Expression in Breast Cancer and Brain Metastasis.

Brain metastasis is a significant challenge for some breast cancer patients, marked by its aggressive nature, limited treatment options, and poor clinical outcomes. Immunotherapies have emerged as a promising avenue for brain metastasis treatment. B7-H3 (CD276) is an immune checkpoint molecule involved in T cell suppression, which is associated with poor survival in cancer patients. Given the increasing number of clinical trials using B7-H3 targeting CAR T cell therapies, we examined B7-H3 expression across breast cancer subtypes and in breast cancer brain metastases to assess its potential as an interventional target. B7-H3 expression was investigated using immunohistochemistry on tissue microarrays of three clinical cohorts: (i) unselected primary breast cancers (n = 347); (ii) brain metastatic breast cancers (n = 61) and breast cancer brain metastases (n = 80, including a subset of 53 patient-matched breast and brain metastasis cases); and (iii) mixed brain metastases from a range of primary tumours (n = 137). In primary breast cancers, B7-H3 expression significantly correlated with higher tumour grades and aggressive breast cancer subtypes, as well as poorer 5-year survival outcomes. Subcellular localisation of B7-H3 impacted breast cancer-specific survival, with cytoplasmic staining also correlating with a poorer outcome. Its expression was frequently detected in brain metastases from breast cancers, with up to 90% expressing B7-H3. However, not all brain metastases showed high levels of expression, with those from colorectal and renal tumours showing a low frequency of B7-H3 expression (0/14 and 2/16, respectively). The prevalence of B7-H3 expression in breast cancers and breast cancer brain metastases indicates potential opportunities for B7-H3 targeted therapies in breast cancer management.

A high-content screen of FDA approved drugs to enhance CAR T cell function: ingenol-3-angelate improves B7-H3-CAR T cell activity by upregulating B7-H3 on the target cell surface via PKCα activation.

BACKGROUND: CAR T cell therapy is a promising approach to improve outcomes and decrease toxicities for patients with cancer. While extraordinary success has been achieved using CAR T cells to treat patients with CD19-positive malignancies, multiple obstacles have so far limited the benefit of CAR T cell therapy for patients with solid tumors. Novel manufacturing and engineering approaches show great promise to enhance CAR T cell function against solid tumors. However, similar to single agent chemotherapy approaches, CAR T cell monotherapy may be unable to achieve high cure rates for patients with difficult to treat solid tumors. Thus, combinatorial drug plus CAR T cell approaches are likely required to achieve widespread clinical success. METHODS: We developed a novel, confocal microscopy based, high-content screen to evaluate 1114 FDA approved drugs for the potential to increase expression of the solid tumor antigen B7-H3 on the surface of osteosarcoma cells. Western blot, RT-qPCR, siRNA knockdown and flow cytometry assays were used to validate screening results and identify mechanisms of drug-induced B7-H3 upregulation. Cytokine and cytotoxicity assays were used to determine if drug pre-treatment enhanced B7-H3-CAR T cell effector function. RESULTS: Fifty-five drugs were identified to increase B7-H3 expression on the surface of LM7 osteosarcoma cells using a novel high-content, high-throughput screen. One drug, ingenol-3-angelate (I3A), increased B7-H3 expression by up to 100%, and was evaluated in downstream experiments. Validation assays confirmed I3A increased B7-H3 expression in a biphasic dose response and cell dependent fashion. Mechanistic studies demonstrated that I3A increased B7-H3 (CD276) mRNA, total protein, and cell surface expression via protein kinase C alpha activation. Functionally, I3A induced B7-H3 expression enhanced B7-H3-CAR T cell function in cytokine production and cytotoxicity assays. CONCLUSIONS: This study demonstrates a novel high-content and high-throughput screen can identify drugs to enhance CAR T cell activity. This and other high-content technologies will pave the way to develop clinical trials implementing rational drug plus CAR T cell combinatorial therapies. Importantly, the technique could also be repurposed for an array of basic and translational research applications where drugs are needed to modulate cell surface protein expression.

Induction of NK cell reactivity against acute myeloid leukemia by Fc-optimized CD276 (B7-H3) antibody.

Acute myeloid leukemia (AML) remains a therapeutic challenge despite recent therapeutic advances. Although monoclonal antibodies (mAbs) engaging natural killer (NK) cells via antibody-dependent cellular cytotoxicity (ADCC) hold promise in cancer therapy, almost none have received clinical approval for AML, so far. Recently, CD276 (B7-H3) has emerged as a promising target for AML immunotherapy, due to its high expression on leukemic blasts of AML patients. Here, we present the preclinical development of the Fc-optimized CD276 mAb 8H8_SDIE with enhanced CD16 affinity. We demonstrate that 8H8_SDIE specifically binds to CD276 on AML cell lines and primary AML cells and induces pronounced NK cell activation and degranulation as measured by CD69, CD25, and CD107a. Secretion of IFNγ, TNF, granzyme B, granulysin, and perforin, which mediate NK cell effector functions, was induced by 8H8_SDIE. A pronounced target cell-restricted lysis of AML cell lines and primary AML cells was observed in cytotoxicity assays using 8H8_SDIE. Finally, xenograft models with 8H8_SDIE did not cause off-target immune activation and effectively inhibited leukemia growth in vivo. We here present a novel attractive immunotherapeutic compound that potently induces anti-leukemic NK cell reactivity in vitro and in vivo as treatment option for AML.

Efficacy of the induced pluripotent stem cell derived and engineered CD276-targeted CAR-NK cells against human esophageal squamous cell carcinoma.

Introduction: Chimeric antigen receptor natural killer (CAR-NK) cells have been found to be successful in treating hematologic malignancies and present potential for usage in solid tumors. Methods: In this study, we created CD276-targeted CAR-expressing NK cells from pluripotent stem cells (iPSC CD276-targeted CAR-NK cells) and evaluated their cytotoxicity against esophageal squamous cell carcinoma (ESCC) using patient-specific organoid (PSO) models comprising of both CD276-positive and CD276-negative adjacent epithelium PSO models (normal control PSO, NC PSO) as well as primary culture of ESCC cell models. In addition, in vitro and in vivo models such as KYSE-150 were also examined. iPSC NK cells and NK-free media were used as the CAR-free and NK-free controls, respectively. Results: The positive CD276 staining was specifically detected on the ESCC membrane in 51.43% (54/105) of the patients of all stages, and in 51.35% (38/74) of stages III and IV. The iPS CD276-targeted CAR-NK cells, comparing with the iPS NK cells and the NK-free medium, exhibited specific and significant cytotoxic activity against CD276-positive ESCC PSO rather than CD276-negative NC PSO, and exhibited significant cytotoxicity against CD276-expressing cultured ESCC cells, as well as against CD276-expressing KYSE-150 in vitro and in BNDG mouse xenograft. Discussion: The efficacy of the iPSC CD276-targeted CAR-NK cells demonstrated by their successful treatment of CD276-expressing ESCC in a multitude of pre-clinical models implied that they hold tremendous therapeutic potential for treating patients with CD276-expressing ESCC.

VISTA checkpoint inhibition by pH-selective antibody SNS-101 with optimized safety and pharmacokinetic profiles enhances PD-1 response.

VISTA, an inhibitory myeloid-T-cell checkpoint, holds promise as a target for cancer immunotherapy. However, its effective targeting has been impeded by issues such as rapid clearance and cytokine release syndrome observed with previous VISTA antibodies. Here we demonstrate that SNS-101, a newly developed pH-selective VISTA antibody, addresses these challenges. Structural and biochemical analyses confirmed the pH-selectivity and unique epitope targeted by SNS-101. These properties confer favorable pharmacokinetic and safety profiles on SNS-101. In syngeneic tumor models utilizing human VISTA knock-in mice, SNS-101 shows in vivo efficacy when combined with a PD-1 inhibitor, modulates cytokine and chemokine signaling, and alters the tumor microenvironment. In summary, SNS-101, currently in Phase I clinical trials, emerges as a promising therapeutic biologic for a wide range of patients whose cancer is refractory to current immunotherapy regimens.

B7-H3 is associated with the armored-cold phenotype and predicts poor immune checkpoint blockade response in melanoma.

Melanoma is the most suitable tumor type for immunotherapy, but not all melanoma patients could respond to immunotherapy. B7 homolog 3 (B7-H3) belongs to the B7 family and is overexpressed in a number of malignant tumors, but the expression pattern of B7-H3 in melanoma has not been well summarized. The expression of B7-H3 was investigated in melanoma and its correlations with features of the tumor microenvironment (TME) by using various public databases, including the Cancer Genome Atlas (TCGA), the GEPIA, and the Human Protein Atlas databases. In addition, the in-house melanoma tissue microarray was applied to validate the results from public databases. Based on the public and in-house cohorts, we found that B7-H3 was overexpressed in melanoma tumor tissues and high B7-H3 expression was related to poor clinical outcome. Moreover, B7-H3 was negatively correlated with levels of tumor-infiltrating lymphocytes (TILs) and positively correlated with collagen infiltration. With clinical translational value, the predictive value of B7-H3 for conventional immunotherapy was detected using the Kaplan-Meier plotter tool, and the results showed that melanoma patients with high B7-H3 expression were insensitive to anti-PD-1 and anti-CTLA-4 immunotherapy. In conclusion, we first investigate the expression of B7-H3 in melanoma and its correlations with the TME features, and indicate B7-H3 as a promising therapeutic target in melanoma patients that are insensitive to conventional immunotherapy.

Exploring the Role and Prognostic Value of TMEM208 in Head and Neck Squamous Cell Carcinoma.

OBJECTIVE: Head and neck squamous cell carcinoma (HNSCC) is one of the world's eight most common malignancies and a severe hazard to human health. Transmembrane protein 208 (TMEM208) has been reported to be associated with autophagy,which is strongly tied to the onset and development of numerous illnesses, including cancer. For this reason, we investigated the expression and prognostic significance of TMEM208 in HNSCC. METHODS: To explore the role and molecular mechanism of this gene in HNSCC, we performed a comprehensive analysis of the TMEM208 gene, including gene expression analysis, prognostic analysis, and immune infiltration analysis using the UALCAN, HPA, CVCDAP, DAVID, TIMER, CIBERSORTx, TISIDB, and cBioPortal online databases. It was further validated by in vitro cell culture. RESULTS: Analysis of TCGA data showed that TMEM208 was highly expressed in HNSCC (P < 0.01) and significantly correlated with several clinicopathologic features, and in vitro cellular assays demonstrated that TMEM208 was highly expressed in multiple squamous carcinoma cell lines. Survival analysis showed that high expression of TMEM208 decreased OS (P=0.0088), PFI (P=0.0062), and DSS (P=0.0036) in HNSCC patients. cox regression analysis indicated that high expression of TMEM208 was an independent risk factor for OS in HNSCC patients (P<0.05). In addition, functional enrichment analysis showed that TMEM208 was closely associated with translation, ribosomal and mitochondrial functions, and GSVA analysis showed that TMEM208 was negatively correlated with a variety of immune cell differentiation in HNSCC, with a statistically significant difference. Immunocorrelation analysis showed that TMEM208 could affect immune cell infiltration in HNSCC; in addition, TMEM208 correlated with CD24, CD276, LAG3, and HVEM. CONCLUSION: In conclusion, TMEM208 holds promise as a prognostic indicator for HNSCC and is closely related to ICI treatment.

Targeting osteosarcoma with canine B7-H3 CAR T cells and impact of CXCR2 Co-expression on functional activity.

The use of large animal spontaneous models of solid cancers, such as dogs with osteosarcoma (OS), can help develop new cancer immunotherapy approaches, including chimeric antigen receptor (CAR) T cells. The goal of the present study was to generate canine CAR T cells targeting the B7-H3 (CD276) co-stimulatory molecule overexpressed by several solid cancers, including OS in both humans and dogs, and to assess their ability to recognize B7-H3 expressed by canine OS cell lines or by canine tumors in xenograft models. A second objective was to determine whether a novel dual CAR that expressed a chemokine receptor together with the B7-H3 CAR improved the activity of the canine CAR T cells. Therefore, in the studies reported here we examined B7-H3 expression by canine OS tumors, evaluated target engagement by canine B7-H3 CAR T cells in vitro, and compared the relative effectiveness of B7-H3 CAR T cells versus B7-H3-CXCR2 dual CAR T cells in canine xenograft models. We found that most canine OS tumors expressed B7-H3; whereas, levels were undetectable on normal dog tissues. Both B7-H3 CAR T cells demonstrated activation and OS-specific target killing in vitro, but there was significantly greater cytokine production by B7-H3-CXCR2 CAR T cells. In canine OS xenograft models, little anti-tumor activity was generated by B7-H3 CAR T cells; whereas, B7-H3-CXCR2 CAR T cells significantly inhibited tumor growth, inducing complete tumor elimination in most treated mice. These findings indicated therefore that addition of a chemokine receptor could significantly improve the anti-tumor activity of canine B7-H3 CAR T cells, and that evaluation of this new dual CAR construct in dogs with primary or metastatic OS is warranted since such studies could provide a critical and realistic validation of the chemokine receptor concept.

EIF2Ss, a Novel c-Myc-Correlated Gene Family, is Associated with Poor Prognosis and Immune Infiltration in Pancreatic Adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is a highly malignant tumor in urgent need of novel diagnostics, prognostic markers, and treatments. Eukaryotic translation initiation factor 2 subunits (EIF2Ss), comprising Eukaryotic translation initiation factor 2 subunit alpha (EIF2S1), Eukaryotic translation initiation factor 2 subunit beta (EIF2S2), and Eukaryotic translation initiation factor 2 subunit gamma (EIF2S3), is a family of eukaryotic initiation factors that participate in early protein synthesis and are crucial for tumor initiation and progression. However, the role of EIF2Ss in PAAD has yet to be reported. The aim of this study was therefore to analyze EIF2Ss in relation to the diagnosis, prognosis, and treatment of PAAD. METHODS: The cancer genome atlas (TCGA) database was used to investigate gene expression and patient survival. Gene alterations, immune cell infiltration, and immune checkpoints in PAAD were also evaluated. Univariate and multivariate analysis, nomograms, calibration curves, and Decision Curve Analysis (DCA) diagrams were used to develop and evaluate a prediction model for patient outcome. Single-cell RNA-seq (scRNA) analysis, functional enrichment, co-IP assay, mass spectrometry, and western blot were used to study the relationship between EIF2Ss and c-myc in PAAD. RESULTS: EIF2Ss are over-expressed in PAAD tissue and are associated with poor prognosis. The frequency of EIF2S1, EIF2S2, and EIF2S3 gene alteration in PAAD was 0.2%, 0.4%, and 0.2%, respectively. High EIF2Ss expression was associated with Th2 cell infiltration, whereas low expression was associated with pDC infiltration. Moreover, EIF2Ss expression was positively correlated with the expression of the NT5E, ULBP1, PVR, CD44, IL10RB, and CD276 checkpoints. A prediction model developed using EIF2Ss and important clinicopathologic features showed good predictive value for the overall survival of PAAD patients. ScRNA-Seq data showed that EIF2Ss was associated with enrichment for endothelial cells, fibroblasts, malignant cells, and ductal cells. EIF2Ss expression was also correlated with adipogenesis, interferon-alpha response, epithelial-mesenchymal transition, myc targets, G2M checkpoint, oxidative phosphorylation, and hypoxia. Functional enrichment analysis of EIF2Ss showed a close correlation with the myc pathway, and interactions between EIF2Ss and c-myc were confirmed by co-IP assay and mass spectrometry. Importantly, knockdown of c-myc decreased the expression of EIF2S1, EIF2S2, and EIF2S3 in PAAD cells. CONCLUSIONS: EIF2Ss were found to have significant clinical implications for the prognosis and treatment of PAAD. Inhibition of c-myc caused the downregulation of EIF2S1, EIF2S2, and EIF2S3 expression.

Clinicopathological features and prognostic value of CD276 expression in female reproductive system malignancies: A meta-analysis.

The relationship between CD276 and malignancies of the female reproductive system has previously been controversial. The purpose of this study was to evaluate the predictive value of CD276 expression in clinicopathological features and prognosis of female reproductive system malignant tumors through meta-analysis. PubMed, Embase, Cochrane Library, Web of Science, CNKI and Wanfang databases were searched for studies published up to December 2022 on the role of CD276 expression in the clinicopathological features and prognosis of female reproductive system malignancies. STATA 14.0 was used for meta-analysis. A total of 10 studies were included, involving 840 patients with malignant tumors of the female reproductive system. The results showed that in terms of clinicopathological features: CD276 expression was closely related to lymph node status [OR = 2.33， 95 %CI = 1.32-4.11， P = 0.003], tumor differentiation [OR = 2.15， 95 %CI = 1.27-3.63, P = 0.004], and FIGO stage [OR = 2.58， 95 %CI = 1.44-4.61, P = 0.001] of reproductive system malignant tumors. In terms of prognosis: CD276 expression is strongly associated with shorter OS in patients with female reproductive system malignancies [HR = 3.33, 95 % CI = 1.36-8.15, P = 0.01]. CD276 may be a new target for immunotherapy and a biomarker for predicting poor prognosis of female reproductive system malignancies.

Expression and function of VISTA on myeloid cells.

V-domain containing Ig Suppressor of T cell Activation (VISTA) is predominantly expressed on myeloid cells and functions as a ligand/receptor/soluble molecule. In inflammatory responses and immune responses, VISTA regulates multiple functions of myeloid cells, such as chemotaxis, phagocytosis, T cell activation. Since inflammation and immune responses are critical in many diseases, VISTA is a promising therapeutic target. In this review, we will describe the expression and function of VISTA on different myeloid cells, including neutrophils, monocytes, macrophages, dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs). In addition, we will discuss whether the functions of VISTA on these cells impact the disease processing.

Vascular characterization reveals immunomodulatory targets for brain metastases.

Brain metastases are clinically challenging due to the unique brain microenvironment. In this issue of Cancer Cell, Bejarano et al. use transcriptional profiling and data integration to shed light on the molecular and cellular composition of the vasculature in brain metastases, identifying CD276 as an immunomodulatory target for therapy.

Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors.

VISTA (V-domain Ig suppressor of T cell activation) is a novel immune checkpoint protein and represents a promising target for cancer immunotherapy. Here, we report the design, synthesis, and evaluation of a series of methoxy-pyrimidine-based VISTA small molecule inhibitors with potent antitumor activity. By employing molecular docking and microscale thermophoresis (MST) assay, we identified a lead compound A1 that binds to VISTA protein with high affinity and optimized its structure. A4 was then obtained, which exhibited the strongest binding ability to VISTA protein, with a KD value of 0.49 ± 0.20 µM. In vitro, A4 significantly activated peripheral blood mononuclear cells (PBMCs) induced the release of cytokines such as IFN-γ and enhanced the cytotoxicity of PBMCs against tumor cells. In vivo, A4 displayed potent antitumor activity and synergized with PD-L1 antibody to enhance the therapeutic effect against cancer. These results suggest that compound A4 is an effective VISTA small molecule inhibitor, providing a basis for the future development of VISTA-targeted drugs.

A promising target for breast cancer: B7-H3.

Breast cancer (BC) is the second-leading factor of mortality for women globally and is brought on by a variety of genetic and environmental causes. The conventional treatments for this disease have limitations, making it difficult to improve the lifespan of breast cancer patients. As a result, extensive research has been conducted over the past decade to find innovative solutions to these challenges. Targeting of the antitumor immune response through the immunomodulatory checkpoint protein B7 family has revolutionized cancer treatment and led to intermittent patient responses. B7-H3 has recently received attention because of its significant demodulation and its immunomodulatory effects in many cancers. Uncontrolled B7-H3 expression and a bad outlook are strongly associated, according to a substantial body of cancer research. Numerous studies have shown that BC has significant B7-H3 expression, and B7-H3 induces an immune evasion phenotype, consequently enhancing the survival, proliferation, metastasis, and drug resistance of BC cells. Thus, an innovative target for immunotherapy against BC may be the B7-H3 checkpoint.In this review, we discuss the structure and regulation of B7-H3 and its double costimulatory/coinhibitory function within the framework of cancer and normal physiology. Then we expound the malignant behavior of B7-H3 in BC and its role in the tumor microenvironment (TME) and finally focus on targeted drugs against B7-H3 that have opened new therapeutic opportunities in BC.

Antibody-Drug Conjugates: Advancing from Magic Bullet to Biological Missile.

Precision drug development is focusing on targeting tumor cell surface proteins for therapeutic delivery, maximizing biomarker identified on-target damage to the tumor while minimizing toxicity. A recent article demonstrated high expression of B7-H4 antigen on resistant ovarian cancer cells and described preclinical activity of B7-H4-directed antibody-drug conjugate. See related article by Gitto et al., p. 1567.

Diagnostic and prognostic value of serum soluble B7-H3 in nonsmall cell lung cancer.

The aim of this study was to investigate the utility of serum soluble B7-H3 (sB7-H3) as a diagnostic marker for early-stage nonsmall cell lung cancer (NSCLC) and its potential for evaluating the prognosis of patients with advanced-stage NSCLC. In this study, an ELISA was employed to detect the expression levels of sB7-H3 in a cohort of patients diagnosed with NSCLC ( n = 122) and a control group ( n = 42) during the same observation period. Comparative analyses were conducted to ascertain the variations in sB7-H3 concentrations between the NSCLC cohort and the healthy control group, as well as across pathological types and the presence and absence of lymph node metastasis. (1) The concentration of sB7-H3 in patients diagnosed with NSCLC exhibited a statistically significant increase compared to that observed in the healthy control group ( P < 0.05). Elevated expression levels of sB7-H3 demonstrated a significant correlation with pathological type, lymph node metastasis, tumor, node and metastasis stage and programmed cell death ligand (PD-L1) expression ( P < 0.05). (2) The diagnostic utility of sB7-H3 for the diagnosis of NSCLC and the heightened expression of PD-L1 demonstrated high levels of sensitivity and specificity. (3) Elevated levels of sB7-H3 emerged as an independent risk factor impacting the overall survival of patients diagnosed with advanced NSCLC. The findings of this study suggest that sB7-H3 holds promise as a diagnostic tool for early-stage NSCLC. The elevated expression of sB7-H3 appears to serve as a reliable indicator for assessing the prognosis of patients diagnosed with advanced NSCLC.

An Fc-modified monoclonal antibody as novel treatment option for pancreatic cancer.

Pancreatic cancer is a highly lethal disease with limited treatment options. Hence, there is a considerable medical need for novel treatment strategies. Monoclonal antibodies (mAbs) have significantly improved cancer therapy, primarily due to their ability to stimulate antibody-dependent cellular cytotoxicity (ADCC), which plays a crucial role in their therapeutic efficacy. As a result, significant effort has been focused on improving this critical function by engineering mAbs with Fc regions that have increased affinity for the Fc receptor CD16 expressed on natural killer (NK) cells, the major cell population that mediates ADCC in humans. Here we report on the preclinical characterization of a mAb directed to the target antigen B7-H3 (CD276) containing an Fc part with the amino acid substitutions S239D/I332E to increase affinity for CD16 (B7-H3-SDIE) for the treatment of pancreatic cancer. B7-H3 (CD276) is highly expressed in many tumor entities, whereas expression on healthy tissues is more limited. Our findings confirm high expression of B7-H3 on pancreatic cancer cells. Furthermore, our study shows that B7-H3-SDIE effectively activates NK cells against pancreatic cancer cells in an antigen-dependent manner, as demonstrated by the analysis of NK cell activation, degranulation and cytokine release. The activation of NK cells resulted in significant tumor cell lysis in both short-term and long-term cytotoxicity assays. In conclusion, B7-H3-SDIE constitutes a promising agent for the treatment of pancreatic cancer.

Interplay between B7-H3 and HLA class I in the clinical course of pancreatic ductal adenocarcinoma.

Human leukocyte antigen (HLA) class I defects are associated with cancer progression. However, their prognostic significance is controversial and may be modulated by immune checkpoints. Here, we investigated whether the checkpoint B7-H3 modulates the relationship between HLA class I and pancreatic ductal adenocarcinoma (PDAC) prognosis. PDAC tumors were analyzed for the expression of B7-H3, HLA class I, HLA class II molecules, and for the presence of tumor-infiltrating immune cells. We observed defective HLA class I and HLA class II expressions in 75% and 59% of PDAC samples, respectively. HLA class I and B7-H3 expression were positively related at mRNA and protein level, potentially because of shared regulation by RELA, a sub-unit of NF-kB. High B7-H3 expression and low CD8+ T cell density were indicators of poor survival, while HLA class I was not. Defective HLA class I expression was associated with unfavorable survival only in patients with low B7-H3 expression. Favorable survival was observed only when HLA class I expression was high and B7-H3 expression low. Our results provide the rationale for targeting B7-H3 in patients with PDAC tumors displaying high HLA class I levels.

Cross-talk between disulfidptosis and immune check point genes defines the tumor microenvironment for the prediction of prognosis and immunotherapies in glioblastoma.

Disulfidptosis is a condition where dysregulated NAPDH levels and abnormal accumulation of cystine and other disulfides occur in cells with high SLC7A11 expression under glucose deficiency. This disrupts normal formation of disulfide bonds among cytoskeletal proteins, leading to histone skeleton collapse and triggering cellular apoptosis. However, the correlation between disulfidptosis and immune responses in relation to glioblastoma survival rates and immunotherapy sensitivity remains understudied. Therefore, we utilized The Cancer Genome Atlas and The Chinese Glioma Genome Atlas to identify disulfidptosis-related immune checkpoint genes and established an overall survival (OS) prediction model comprising six genes: CD276, TNFRSF 14, TNFSF14, TNFSF4, CD40, and TNFRSF18, which could also be used for predicting immunotherapy sensitivity. We identified a cohort of glioblastoma patients classified as high-risk, which exhibited an upregulation of angiogenesis, extracellular matrix remodeling, and epithelial-mesenchymal transition as well as an immunosuppressive tumor microenvironment (TME) enriched with tumor associated macrophages, tumor associated neutrophils, CD8 + T-cell exhaustion. Immunohistochemical staining of CD276 in 144 cases further validated its negative correlation with OS in glioma. Disulfidptosis has the potential to induce chronic inflammation and an immunosuppressive TME in glioblastoma.

Comprehensive analysis of PSME3: from pan-cancer analysis to experimental validation.

PSME3 plays a significant role in tumor progression. However, the prognostic value of PSME3 in pan-cancer and its involvement in tumor immunity remain unclear. We conducted a comprehensive study utilizing extensive RNA sequencing data from the TCGA (The Cancer Genome Atlas) and GTEx (Genotype-Tissue Expression) databases. Our research revealed abnormal expression levels of PSME3 in various cancer types and unveiled a correlation between high PSME3 expression and adverse clinical outcomes, especially in cancers like liver cancer (LIHC) and lung adenocarcinoma (LUAD). Functional enrichment analysis highlighted multiple biological functions of PSME3, including its involvement in protein degradation, immune responses, and stem cell regulation. Moreover, PSME3 showed associations with immune infiltration and immune cells in the tumor microenvironment, indicating its potential role in shaping the cancer immune landscape. The study also unveiled connections between PSME3 and immune checkpoint expression, with experimental validation demonstrating that PSME3 positively regulates CD276. This suggests that PSME3 could be a potential therapeutic target in immunotherapy. Additionally, we predicted sensitive drugs targeting PSME3. Finally, we confirmed in both single-factor Cox and multiple-factor Cox regression analyses that PSME3 is an independent prognostic factor. We also conducted preliminary validations of the impact of PSME3 on cell proliferation and wound healing in liver cancer. In summary, our study reveals the multifaceted role of PSME3 in cancer biology, immune regulation, and clinical outcomes, providing crucial insights for personalized cancer treatment strategies and the development of immunotherapy.