• B7 homolog 3
• Immunotherapy
• Pancreatic cancer
• Prognosis
• Signaling pathways

• Humans
• Pancreatic Neoplasms/immunology
• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/therapy
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/mortality
• B7 Antigens/metabolism
• B7 Antigens/antagonists & inhibitors
• B7 Antigens/immunology
• Animals
• Drug Resistance, Neoplasm/immunology
• Immune Checkpoint Inhibitors/therapeutic use
• Immune Checkpoint Inhibitors/pharmacology
• Immunotherapy/methods
• Antineoplastic Agents, Immunological/therapeutic use
• Antibodies, Monoclonal/therapeutic use

• B7-H3
• Biomarker
• Bladder cancer
• Clinicopathological characteristics
• meta-analysis

• Humans
• Prognosis
• Urinary Bladder Neoplasms
• Proportional Hazards Models
• Urinary Bladder
• Biomarkers, Tumor

• HB2020013 Taihu Talents Scheme of China

• B7-H3
• NK cells
• immunotherapy
• pancreatic cancer
• therapeutic antibody

• Humans
• Immunotherapy/methods
• Antibody-Dependent Cell Cytotoxicity
• Antibodies, Monoclonal
• Killer Cells, Natural
• Pancreatic Neoplasms/metabolism
• B7 Antigens/metabolism

• ADCs
• B7-H3
• checkpoint inhibitors
• immune checkpoints
• immunotherapy
• solid malignancies

• ADCC
• B7-H3
• Esophageal squamous cell carcinoma
• Fc engineering
• monoclonal antibody

• Humans
• Animals
• Mice
• Esophageal Squamous Cell Carcinoma/drug therapy
• Esophageal Neoplasms/drug therapy
• Antibodies, Monoclonal, Humanized/pharmacology
• Antibodies, Monoclonal/pharmacology
• Antibody-Dependent Cell Cytotoxicity

• proteomics
• mass spectrometry

• Humans
• Proteome
• Proteomics
• Triple Negative Breast Neoplasms
• Docetaxel
• Membrane Proteins
• Transcription Factors
• B7 Antigens

• National Research Foundation of Korea

• B7-H3
• IMPDH2
• cell survival
• cell–cell adhesion
• chemoresistance
• invasion
• lung cancer
• oxidative stress
• proliferation
• rods and rings

• MC_PC_12025 Medical Research Council
• MR/W031469/1 Medical Research Council

• immunosurveillance
• cell signalling
• tumour immunology

• Humans
• Tumor Escape
• T-Lymphocytes
• Genes, Regulator
• Transcription Factors
• Mechanistic Target of Rapamycin Complex 1
• B7 Antigens

• K08 AR077037 NIAMS NIH HHS
• U01 HL131022 NHLBI NIH HHS
• U.S. Department of Defense (United States Department of Defense)
• LAM Foundation
• U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
• Engles Family TSC/LAM Research Fund Lee Family Research Fund

• CRISPR-Cas9 cancer immunotherapy
• cancer therapeutic strategy
• cancer treatment
• immune checkpoint inhibitors
• immune response
• immune-oncology
• mRNA cancer immunotherapy
• tumor immune escape
• tumor immune microenvironment

• B7-H3 (CD276)
• CD3
• bispecific antibody
• gastric cancer
• gastrointestinal cancer
• hepatic cancer
• immunotherapy
• pancreatic cancer

• B7 family
• cancer immunotherapy
• immune checkpoint
• novel targeted immunotherapies
• pancreatic ductal adenocarcinoma

• Humans
• B7-H1 Antigen
• Carcinoma, Pancreatic Ductal/drug therapy
• Carcinoma, Pancreatic Ductal/genetics
• Immunoglobulins/pharmacology
• Immunotherapy
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Tumor Microenvironment

• Binding pocket analysis
• Inhibitory immune checkpoints
• PD-1/PD-L1
• SAR
• Small molecule inhibitors

Retinoblastoma is the most common intraocular tumor in children. Patients can be cured by enucleation, but it can lead to vision loss. Chemotherapy is the main method of treatment for RB currently. Unfortunately, chemoresistant and tumor metastasis often happen, resulting in a relatively poor prognosis. Therefore, immunotherapy becomes one of the optimal choices. Targeting not only tumor cells but also the active tumor microenvironment is a novel strategy for RB treatment. Here, we conclude several potential targets for RB immunotherapy, including gangliosides GD2, PD-1 and PD-L1, B7H3, EpCAM and SYK. We also review the techniques for CART, bispecific antibodies and genetically modified Dendritic cells according to the characteristics of different targets and discuss the feasibility of immunotherapy with different targets.

Prostate cancer is one of the most common malignant tumors in men. Initially, it is androgen-dependent, but it eventually develops into castration-resistant prostate cancer (CRPC), which is incurable with current androgen receptor signaling target therapy and chemotherapy. Immunotherapy, specifically with immune checkpoint inhibitors, has brought hope for the treatment of this type of prostate cancer. Approaches such as vaccines, adoptive chimeric antigen receptor-T (CAR-T) cells, and immune checkpoint inhibitors have been employed to activate innate and adaptive immune responses to treat prostate cancer, but with limited success. Only Sipuleucel-T and the immune checkpoint inhibitor pembrolizumab are approved by the US FDA for the treatment of limited prostate cancer patients. Prostate cancer has a complex tumor microenvironment (TME) in which various immunosuppressive molecules and mechanisms coexist and interact. Additionally, prostate cancer is considered a “cold” tumor with low levels of tumor mutational burden, low amounts of antigen-presenting and cytotoxic T-cell activation, and high levels of immunosuppressive molecules including cytokines/chemokines. Thus, understanding the mechanisms of immunosuppressive signaling activation and immune evasion will help develop more effective treatments for prostate cancer. The purpose of this review is to summarize emerging advances in prostate cancer immunotherapy, with a particular focus on the molecular mechanisms that lead to immune evasion in prostate cancer. At the same time, we also highlight some potential therapeutic targets to provide a theoretical basis for the treatment of prostate cancer.

• B7-H3
• CAR-T
• solid tumors

Immunotherapy only achieves efficacy in some cancer patients, and less is known about other immune checkpoint molecules in chordoma. Here, we aimed to determine the expression of PD-L1, HHLA2, B7H3, IDO-1 and Galectin-9 in spinal chordoma and evaluated their association with tumor infiltrating lymphocytes (TILs), clinicopathological characteristics and survival of patients.

Using multiplexed quantitative immunofluorescence (QIF), we simultaneously measured the levels of five different immune checkpoint molecules and major TIL subsets in 92 human spinal chordoma samples.

Tumor HHLA2 and PD-L1 were positive in 80.0% and 86.0% of cases, respectively. However, B7H3, IDO-1 and Galectin-9 positivity on tumor cells were only seen in 21.0% of cases, despite all showing predominantly stromal expression. Coexpression of these QIF markers in the tumor compartment was scarcely detected except for PD-L1 and HHLA2, which was observed in 69.6% of cases. While tumoral HHLA2 and stromal B7H3 expressions were associated with an aggressive tumor phenotype, suppressive immune response (specifically including elevated PD-1⁺ TILs level and decreased CD8⁺ TIL density) and poor prognosis, stromal levels of PD-L1 and Galectin-9 predicted the opposite outcomes. Importantly, HHLA2 and PD-L1 coexpression on tumor cells independently predicted both worse local recurrence-free survival and overall survival.

These data provide a better understanding of the immunosuppressive mechanism in chordoma and may be useful for the development of combination or novel immunotherapy approaches aiming to improve therapeutic efficacy and survival.

• HHLA2
• PD-L1
• immune checkpoint molecules
• quantitative immunofluorescence
• spinal chordoma
• tumor infiltrating lymphocytes

Immunotherapy is a novel hotspot for the treatment of pancreatic adenocarcinoma (PAAD). However, potential biomarkers which could identify the inflamed tumor microenvironment (TME) are urgently required.

In the present study, we measured the levels of B7-H3, B7-H4, and major tumor-infiltrating immune cells (TIICs) using bioinformatics analyses and immunohistochemistry (IHC) staining on PAAD samples represented in the tissue microarray (TMA) format. Statistical analysis and figures exhibition were performed using R 4.1.0, SPSS 26.0, and GraphPad Prism 6.0.

B7-H3 and B7-H4 were up-regulated in PAAD compared with para-tumor tissues, and their expression exhibited no tight correlation in PAAD tissues. B7-H3 and B7-H4 were lowly expressed in well-differentiated PAAD tissues and correlated with poorly differentiated grades. Besides, single B7-H3 or B7-H4 expression exhibited limited prognostic value, but co-deficiency of B7-H3 and B7-H4 predicted a better prognosis in PAAD. Moreover, co-deficiency of B7-H3 and B7-H4 indicated immuno-hot tumors with high CD8 + T cell infiltration.

Overall, combined B7-H3 and B7-H4 expression is a promising stratification strategy to assess prognosis and immunogenicity in PAAD, which could be used as a novel classifier in clinical practice.

The online version contains supplementary material available at 10.1186/s12885-022-09294-w.

• cancer
• glycolysis
• immunology
• metabolism

• Citric Acid Cycle
• Glycolysis/physiology
• Humans
• Neoplasms/metabolism

• F30 CA247202 NCI NIH HHS
• R01 CA217987 NCI NIH HHS
• T32 GM007347 NIGMS NIH HHS
• T32 GM152284 NIGMS NIH HHS
• U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)

4IgB7-H3 (4Ig) and 2IgB7-H3 (2Ig) expression characteristics in acute myeloid leukemia (AML) remain unknown. This study investigated mRNA and membrane protein expression of two B7-H3 isoforms in AML cell lines and de novo patients by using RT-PCR and flow cytometry, and analyzed the B7-H3 promoter methylation state by utilizing RQ-MSP. 4Ig was the dominant isoform. 2Ig mRNA expression rate and abundance were elevated in AML in comparison with controls (P = 0.000 and 0.000), while no significant difference in 4Ig (P = 0.802, P = 0.398). Membrane protein levels of B7-H3 isoforms in AML was higher than controls, detected by total B7-H3 expression rate (P = 0.002), total B7-H3 mean fluorescence intensity (MFI) ratio of blast cells and lymphocytes (MFI ratio) (P = 0.000), and 4Ig B7-H3 MFI ratio (P = 0.005). Compared with 2Ig^low group, 2Ig^high patients had older age, lower NPM1 mutation, higher FLT3-ITD mutation, and declining complete remission (CR) rates (P = 0.026, 0.012, 0.047, and 0.028). In B7-H3^high group, there was a trend toward older age, M4 and M5, worse karyotype, and lower CR rates, although with no marked difference (P > 0.05). The overall survival (OS) of 2Ig^high and B7-H3^high groups were shorter than that of 2Ig^low and B7-H3^low groups in the whole and non-M3 AML cohorts (P = 0.006 and 0.046; P = 0.003 and 0.032). Besides, an unmethylated B7-H3 promoter was identified. In conclusion, 2Ig mRNA and total B7-H3 membrane protein tended to have potential diagnostic value for AML. Specifically, high 2Ig mRNA and total B7-H3 membrane protein expression indicate worse OS. 4Ig and 2Ig expression are methylation-independent.

• 2Ig B7-H3
• 4Ig B7-H3
• acute myeloid leukemia
• prognosis

B7 homolog 3 (B7-H3) is a recently found superfamily B7 molecule and therefore has significant involvement in immunological regulation. However, the relationships of B7-H3 expression with the tumor microenvironment (TME), response to immunotherapy, and prognosis in head and neck squamous cell carcinoma (HNSCC) are still unknown. In the present analysis, we determined B7-H3 as a novel biomarker that predicts the prognosis and response to immunotherapy in HNSCC. B7-H3 expression is enhanced in HNSCC compared to normal sample and is stably expressed in HNSCC cell line. Besides, high B7-H3 expression is correlated with a dismal prognosis and resistance to immunotherapy and contributes to an immunosuppressive microenvironment. Moreover, single-cell RNA sequencing (scRNA-seq) analysis shows that B7-H3 is mainly expressed in the stromal as well as malignant cells. In conclusion, the study provides insight in understanding the prognostic value of B7-H3 in HNSCC and highlights its involvement in promoting the immunosuppressive microenvironment, which presents an attractive strategy for antibody-based immunotherapy.

• B7-H3
• HNSCC
• immune checkpoint
• immunotherapy
• prognostic biomarker

Medullary thyroid cancer (MTC) is a rare malignancy that arises from calcitonin-producing C-cells. Curative treatment for patients with metastatic MTC is challenging. Identifying the mechanisms by which cancer cells inhibit the activity of immune cells provides an opportunity to develop new therapies that restore anticancer activity. Little is known about the immunological phenomena underlying MTC. Here, we examined the expression profile of 395 genes associated with MTC. The study included 51 patients diagnosed with MTC at a single center. Bioinformatical analysis revealed that CD276 expression in MTC cells was at least three-fold higher than that in normal tissue. The expression of CD276 showed a weak but statistically significant positive correlation with tumor diameter, but we did not find a significant association between CD276 expression and other histopathological clinical factors, or the response to initial therapy. A search of published data identified the monoclonal antibody (inhibitor) enoblituzumab as a potential drug for patients diagnosed with MTC overexpressing CD276.

• CD276
• immunotherapy
• medullary thyroid cancer

• B7-H3
• Colon cancer
• Immunotherapy
• MiR-29a

• Aged
• Aged, 80 and over
• Animals
• B7 Antigens/genetics
• B7 Antigens/metabolism
• Caco-2 Cells
• Cell Movement
• Cell Proliferation
• Colonic Neoplasms/genetics
• Colonic Neoplasms/metabolism
• Colonic Neoplasms/mortality
• Colonic Neoplasms/pathology
• Disease Progression
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Lymphatic Metastasis
• Male
• Mice, Inbred BALB C
• MicroRNAs/agonists
• MicroRNAs/antagonists & inhibitors
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Middle Aged
• Neoplasm Staging
• Oligoribonucleotides/genetics
• Oligoribonucleotides/metabolism
• Signal Transduction
• Survival Analysis
• Xenograft Model Antitumor Assays
• Mice

• no. 31770985 National Natural Science Foundation of China
• no.82073180 National Natural Science Foundation of China
• no. BE2019665 Jiangsu Provincial Key Research and Development Program
• no. QNRC2016732 Jiangsu Provincial Medical Youth Talent
• no. 2016-WSW-043 Six Talent Peaks Project in Jiangsu Province

Bladder cancer is a frequent malignancy and has a clinical need for new therapeutic approaches. Antibody and protein technologies came a long way in recent years and new engineering approaches were applied to generate innovative therapeutic entities with novel mechanisms of action. Furthermore, mRNA-based pharmaceuticals recently reached the market and CAR-T cells and viral-based gene therapy remain a major focus of biomedical research. This review focuses on the engineering of biologics, particularly therapeutic antibodies and their application in preclinical development and clinical trials, as well as approved monoclonal antibodies for the treatment of bladder cancer. Besides, newly emerging entities in the realm of bladder cancer like mRNA, gene therapy or cell-based therapeutics are discussed and evaluated. As many discussed molecules exhibit unique mechanisms of action based on innovative protein engineering, they reflect the next generation of cancer drugs. This review will shed light on the engineering strategies applied to develop these next generation treatments and provides deeper insights into their preclinical profiles, clinical stages, and ongoing trials. Furthermore, the distribution and expression of the targeted antigens and the intended mechanisms of action are elucidated.

• ADC
• antibody engineering
• bladder cancer
• immuno-oncology
• immunotherapy
• protein engineering
• recombinant viral vector vaccines
• urothelial carcinoma

Intratumoral hypoxia is a widely established element of the pancreatic tumor microenvironment (TME) promoting immune escape, tumor invasion, and progression, while contributing to treatment resistance and poor survival. Despite this critical role, hypoxia is underrepresented in molecular signatures of pancreatic ductal adenocarcinoma (PDA) and concurrent investigations into the hypoxia-immune status are lacking. In this work a literature-based approach was applied to derive an eight-gene hypoxia signature that was validated in fourteen cancer cell lines and in a cohort of PDA. The eight-gene hypoxia signature was significantly associated with overall survival in two distinct PDA datasets and showed independent prognostic value in multivariate analysis. Comparative analysis of tumors according to their hypoxia score (high versus low) determined that tumors with high hypoxia were significantly less enriched in cytotoxic T-cells, and cytolytic activity. In addition, they had lower expression of cytokines and tumor inflammatory markers, pointing to the signature’s ability to discern an immune “cold”, hypoxic TME. Combining the signature with an immune metric highlighted a worse survival probability in patients with high hypoxia and low immune reactivity, indicating that this approach could further refine survival estimates. Hypoxia as determined by our signature, was significantly associated with certain immune checkpoint inhibitors (ICI) biomarkers, suggesting that the signature reflects an aspect of the TME that is worth pursuing in future clinical trials. This is the first work of its kind in PDA, and our findings on the hypoxia-immune tumor contexture are not only relevant for ICI but could also guide combinatorial hypoxia-mediated therapeutic strategies in this cancer type.

• hypoxia
• immunosuppresive
• immunotharapy
• microenvironment
• pancreatic cancer
• prognostic
• signature
• tumor inflammation

• B7-H3
• immunotherapy
• monoclonal antibody
• tumor antigen

• Antibodies, Monoclonal/therapeutic use
• Antigens, Neoplasm
• B7 Antigens
• Humans
• Immunotherapy
• Neoplasms/therapy

• R01 DE028172 NIDCR NIH HHS
• R03 CA223886 NCI NIH HHS
• R03 CA231766 NCI NIH HHS
• R03 CA249542 NCI NIH HHS

B7-H3 is an immunomodulatory member of the B7-superfamily with limited expression in normal tissues, but overexpression in several types of cancer. Therefore it is currently being explored as a potential target for cancer immunotherapy. The biological relevance of B7-H3 expression in pancreatic cancer is unclear, while there are no data on B7-H3 expression in ampullary cancer. We aimed to compare intra-tumoral B7-H3 expression between these two closely related cancer types and analyze its association with post-surgical disease course. B7-H3 expression levels were determined by immunohistochemistry in tissue microarrays of resected tumors of 137 pancreatic cancer patients and 83 patients with ampullary cancer of the pancreato-biliary subtype. B7-H3 was more frequently expressed in cancer cells of ampullary cancer patients compared to pancreatic cancer patients (51% versus 21%; p< 0.001). In ampullary cancer patients, but not in pancreatic cancer patients, B7-H3 cancer cell expression was associated with longer disease-free survival and patient survival. However, the prognostic value of B7-H3 was lost upon adjustment for CA19-9 levels. The frequencies of B7-H3 expression in tumor stroma did not differ between the two types of cancer (66% versus 63%). In both cancer types, stromal B7-H3 expression was not associated with post-surgical disease course. Compared to pancreatic cancer, B7-H3 is more frequently expressed in cancer cells of patients with the pancreato-biliary subtype of ampullary cancer. These data suggest that B7-H3 may represent an interesting potential target for immunotherapy in ampullary cancer rather than in pancreatic cancer.

• B7H3
• CD276
• cancer immunotherapy
• immune checkpoint
• pancreas

Short survival of glioblastoma (GBM) patients is due to systematic tumor recurrence. Our laboratory identified a GBM cell subpopulation able to leave the tumor mass (TM) and invade the subventricular zone (SVZ-GBM cells). SVZ-GBM cells escape treatment and appear to contribute to GBM recurrence. This study aims to identify proteins specifically expressed by SVZ-GBM cells and to define their role(s) in GBM aggressiveness and recurrence. The proteome was compared between GBM cells located in the initial TM and SVZ-GBM cells using mass spectrometry. Among differentially expressed proteins, we confirmed B7-H3 by western blot (WB) and quantitative RT-PCR. B7-H3 expression was compared by immunohistochemistry and WB (including expression of its isoforms) between human GBM (N = 14) and non-cancerous brain tissue (N = 8), as well as newly diagnosed GBM and patient-matched recurrences (N = 11). Finally, the expression of B7-H3 was modulated with short hairpin RNA and/or over-expression vectors to determine its functional role in GBM using in vitro assays and a xenograft mouse model of GBM. B7-H3 was a marker for SVZ-GBM cells. It was also increased in human GBM pericytes, myeloid cells and neoplastic cells. B7-H3 inhibition in GBM cells reduced their tumorigenicity. Out of the two B7-H3 isoforms, only 2IgB7-H3 was detected in non-cancerous brain tissue, whereas 4IgB7-H3 was specific for GBM. 2IgB7-H3 expression was higher in GBM recurrences and increased resistance to temozolomide-mediated apoptosis. To conclude, 4IgB7-H3 is an interesting candidate for GBM targeted therapies, while 2IgB7-H3 could be involved in recurrence through resistance to chemotherapy.

• B7-H3
• Glioblastoma
• Isoforms
• Recurrence

• B7-H3
• CD276
• progression
• therapeutic target
• tumor

• Breast Cancer Biology
• Chemoresistance
• Immune checkpoint
• Therapeutic molecules

Pancreatic cancer (PC) is one of the most deadly cancers worldwide. To uncover the unknown novel biomarker used to indicate early diagnosis and prognosis in the molecular therapeutic field of PC is extremely of importance. Accumulative evidences indicated that aberrant expression or activation of immunoinhibitors is a common phenomenon in malignances, and significant associations have been noted between immunoinhibitors and tumorigenesis or progression in a wide range of cancers. However, the expression patterns and exact roles of immunoinhibitors contributing to tumorigenesis and progression of pancreatic cancer (PC) have not yet been elucidated clearly. In this study, we investigated the distinct expression and prognostic value of immunoinhibitors in patients with PC by analyzing a series of databases, including TISIDB, GEPIA, cBioPortal, and Kaplan-Meier plotter database. The mRNA expression levels of IDO1, CSF1R, VTCN1, KDR, LGALS9, TGFBR1, TGFB1, IL10RB, and PVRL2 were found to be significantly upregulated in patients with PC. Aberrant expression of TGFBR1, VTCN1, and LGALS9 was found to be associated with the worse outcomes of patients with PC. Bioinformatics analysis demonstrated that LGALS9 was involved in regulating the type I interferon signaling pathway, interferon-gamma-mediated signaling pathway, RIG-I-like receptor signaling pathway, NF-kappa B signaling pathway, cytosolic DNA-sensing pathway, and TNF signaling pathway. And TGFB1 was related to mesoderm formation, cell matrix adhesion, TGF-beta signaling pathway, and Hippo signaling pathway. These results suggested that LGALS9 and TGFBR1 might serve as potential prognostic biomarkers and targets for PC.

Immune checkpoints comprise diverse receptors and ligands including costimulatory and inhibitory molecules, which play monumental roles in regulating the immune system. Immune checkpoints retain key potentials in maintaining the immune system homeostasis and hindering the malignancy development and autoimmunity. The expression of inhibitory immune checkpoints delineates an increase in a plethora of metastatic tumors and the inhibition of these immune checkpoints can be followed by promising results. On the other hand, the stimulation of costimulatory immune checkpoints can restrain the metastasis originating from diverse tumors. From the review above, key findings emerged regarding potential functions of inhibitory and costimulatory immune checkpoints targeting the metastatic cascade and point towards novel potential Achilles’ heels of cancer that might be exploited therapeutically in the future.

• Immune checkpoints
• Immune system
• Metastasis
• Tumor

• B7-H3 Immune
• anti-cancer immune response
• body fluids
• isoform
• pro-tumorigenic activities
• regulators

• B7-H3
• CD276
• TMA
• prognosis
• prostate cancer

• Adenosine A2a receptor (A2aR)
• B and T lymphocyte associated (BTLA)
• B7 homolog 3 protein (B7-H3)
• B7 homolog 4 protein (B7-H4)
• Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4)
• Immune-regulatory molecule indoleamine pyrrole-2,3-dioxygenase-1,2 (IDO)
• Lymphocyte Activation Gene-3 (LAG-3)
• Programmed Cell Death 1 (PD-1)
• Programmed Death- Ligand 1 (PD-L1)
• T cell immunoglobulin and mucin domain 3 (TIM-3)
• V-domain Ig suppressor of T cell activation (VISTA).

• Blood cancers
• Cancer treatment
• Human immune system
• Immune checkpoint

Retinoblastoma (RB) is the most common paediatric intraocular tumour. Currently, chemotherapy is widely used to reduce the chance of metastasis as well as for vision salvage. The limitations of chemotherapy for RB include chemoresistance and cytotoxicity. Recently, immunotherapy is considered for treating chemoresistant cancers. Although, several molecular targets are available for immunotherapy in different cancers, we were interested in B7H3, as it was differentially expressed between retinoblastoma and retina in our earlier proteomics study. Hence, in this study we validated the previous finding by Western blotting and immunohistochemistry on primary RB tumor samples. The results suggest significantly increased expression of B7H3 in RB tumor samples compared to retina by western blotting. Immunohistochemistry revealed spatial, inter and intratumoral heterogeneity in the primary RB tumor sections. Correlation of the B7H3 expression with clinical and histopathological data revealed significantly increased expression of B7H3 in poorly differentiated, non-neural invasive tumors and lower expression in neural invasion and severe anaplastic areas of the tumors. B7H3 expression did not significantly vary between low-risk and high-risk tumors. The study also revealed considerably reduced infiltration of T lymphocytes in RB. We conclude that B7H3 is prominently expressed in primary RB tumors and could be used for targeted therapy.

• B7-H3
• CD276
• antibody
• cancer immunotherapy
• immune checkpoint

• Autoimmune disease
• Epithelial–mesenchymal transition
• Immune checkpoint
• Inflammation
• Self-tolerance

• B7-H1 Antigen/immunology
• B7-H1 Antigen/metabolism
• Cell Cycle Checkpoints/immunology
• Epithelial-Mesenchymal Transition
• Humans
• Immune Evasion/immunology
• Immune Tolerance/immunology
• Neoplasms/immunology
• Neoplasms/metabolism
• Receptors, Immunologic/immunology
• Receptors, Immunologic/metabolism
• T-Lymphocytes/immunology

• Lead-203
• Lead-212
• MIRD
• Pb-203
• Pb-212
• Radiopharmaceuticals
• SPECT imaging
• cancer
• dosimetry
• radiochemistry
• radionuclide therapy
• theranostics
• voxel-based dosimetry

• Bismuth
• Humans
• Lead Radioisotopes/therapeutic use
• Neoplasms/diagnostic imaging
• Neoplasms/radiotherapy
• Precision Medicine
• Radioisotopes
• Radiopharmaceuticals/therapeutic use
• Tissue Distribution

• P30 CA086862 NCI NIH HHS
• P50 CA174521 NCI NIH HHS
• R01 CA243014 NCI NIH HHS

The application of chimeric antigen receptor (CAR)-T cell therapy in patients with advanced solid tumors remains a significant challenge. Simultaneously targeting antigen and the solid tumor microenvironment are two major factors that greatly impact CAR-T cell therapy outcomes. In this study, we engineered CAR-T cells to specifically target B7-H3, a protein commonly found in solid human tumors, using a single-chain variable fragment (scFv) derived from an anti-B7-H3 monoclonal antibody. We tested the antitumor activity of B7-H3 CAR-T cells in mouse models with solid human tumors and determined that B7-H3 CAR-T cells exhibited potent antitumor activity against B7-H3⁺ tumor cells in vitro and in vivo. In addition, PD-1 decoy receptors were engineered to include extracellular PD-1 fused to the intracellular stimulatory domain of either CD28 or IL-7 receptor, respectively, which were then introduced into B7-H3 CAR-T cells. As a result, these newly modified, superior CAR-T cells exhibited more persistent antitumor activity in B7-H3⁺/B7-H1⁺ tumors in vivo. Our findings indicate that B7-H3 specific CAR-T cells have the potential to treat multiple types of advanced solid tumors.

• B7-H3
• CAR-T cells
• IL-7R
• PD-1
• cancer immunotherapy

Acidic microenvironments exist widely in tumors. However, the specific mechanism of cancer cell survival under an acidic microenvironment remains unknown. This study aims to investigate whether acid can induce autophagy and examine the mechanism of autophagy in gastric cancer cells.

Human gastric adenocarcinoma (AGS) cells were cultured in media with different pH values in vitro and then subjected to autophagy detection under different conditions. To determine the effect of an acidic microenvironment on autophagy, we employed real-time quantitative polymerase chain reaction (PCR), Western blot, mRFP-GFP-LC3 immunofluorescence, and transmission electron microscopy (TEM) to detect the expression of various autophagy indicators. We also performed cell counting kit 8 (CCK8) and cell invasion and migration assays to examine cell viability and invasion, respectively.

We found that the protein expression of autophagy markers such as LC3II/I and Beclin1 was higher in AGS cells treated with an acidic microenvironment than in control cells. The protein expression level of P62 was obviously decreased in acid-treated cells compared to that in control cells. Furthermore, the expression of Erk1/2 pathway markers, including p-Erk1/2, was also increased in response to acidic pH. Dense LC3 puncta were observed in cells cultured under acidic conditions, whereas untreated cells exhibited diffuse and weak LC3 puncta; an increased autophagy flux could also be observed. The presence of autophagosomes was observed by TEM in AGS cells subjected to low pH. Additionally, autophagy was inhibited by the autophagy inhibitor Bafilomycin A1 (Baf) and apoptosis was obviously increased. Moreover, cells exposed to an acidic microenvironment displayed facilitated growth compared with that in control cells.

Taken together, these results indicate that the acidic microenvironment promotes AGS cell growth by upregulating autophagy through the Erk1/2 pathway, which acts as a survival adaptation.

• Gastric cancer
• acidic microenvironment
• apoptosis
• autophagy

• CD276
• SNP
• acute rejection
• costimulatory molecule
• liver transplantation

• Adult
• B7 Antigens/genetics
• B7 Antigens/metabolism
• Female
• Graft Rejection/epidemiology
• Graft Rejection/genetics
• Hepatitis B/epidemiology
• Humans
• Liver Transplantation/adverse effects
• Male
• Middle Aged
• Models, Genetic
• Models, Statistical
• Polymorphism, Single Nucleotide
• Receptors, Immunologic/genetics