• CD276
• MEK/ERK
• Nimotuzumab
• Tumor-infiltrating lymphocytes (TILs)
• head and neck squamous cell carcinoma (HNSCC)

• Animals
• Humans
• B7 Antigens/metabolism
• B7 Antigens/genetics
• B7 Antigens/immunology
• B7 Antigens/antagonists & inhibitors
• Squamous Cell Carcinoma of Head and Neck/drug therapy
• Squamous Cell Carcinoma of Head and Neck/immunology
• Antibodies, Monoclonal, Humanized/pharmacology
• Antibodies, Monoclonal, Humanized/therapeutic use
• Cell Line, Tumor
• Head and Neck Neoplasms/drug therapy
• Head and Neck Neoplasms/immunology
• Mice
• Xenograft Model Antitumor Assays
• Tumor Escape/drug effects
• Antineoplastic Agents, Immunological/pharmacology
• Antineoplastic Agents, Immunological/therapeutic use
• Mice, Inbred BALB C
• Mice, Nude
• ErbB Receptors/metabolism
• ErbB Receptors/antagonists & inhibitors
• Lymphocytes, Tumor-Infiltrating/immunology
• Lymphocytes, Tumor-Infiltrating/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• Tumor Microenvironment/drug effects
• Tumor Microenvironment/immunology
• Female

• EZH2
• Hepatocellular carcinoma (HCC)
• Pathomics
• Pathomics score (PS)
• Survival

• B7‐H3
• high‐intensity focused ultrasound
• liver cancer
• microbubble
• ultrasound molecular imaging

• Microbubbles
• B7 Antigens/metabolism
• Animals
• Liver Neoplasms/diagnostic imaging
• Liver Neoplasms/therapy
• Liver Neoplasms/pathology
• High-Intensity Focused Ultrasound Ablation/methods
• Mice
• Molecular Imaging/methods
• Humans
• Ultrasonography/methods
• Contrast Media
• Cell Line, Tumor
• Mice, Inbred BALB C

• CYS22346 Chongqing Graduate Student Research Innovation Project
• cstb2022nscq-msxc324 Natural Science Foundation of Chongqing, China
• cstc2020jcyj-msxmX0538 Natural Science Foundation of Chongqing, China
• 81971633 National Natural Science Foundation of China
• 82272025 National Natural Science Foundation of China
• Chongqing Graduate Student Research Innovation Project
• Natural Science Foundation of Chongqing, China
• National Natural Science Foundation of China

• Antibody-drug conjugates
• Biliary tract cancer
• Cholangiocarcinoma
• Hepatocellular carcinoma
• Pancreatic adenocarcinoma
• Targeted therapies

• Humans
• Immunoconjugates/therapeutic use
• Biliary Tract Neoplasms/drug therapy
• Pancreatic Neoplasms/drug therapy
• Liver Neoplasms/drug therapy
• Antineoplastic Agents, Immunological/therapeutic use

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

• AC12-GGGC
• Affibody molecule
• Affinity maturation
• B7-H3
• Peptide-based cysteine-containing chelator
• SKOV-3 xenograft
• SPECT/CT imaging
• Technetium-99m ((99m)Tc)
• –GGGC

• Humans
• Animals
• Mice
• Immune Checkpoint Proteins/metabolism
• Tissue Distribution
• Technetium/chemistry
• Radionuclide Imaging
• Neoplasms/metabolism
• Cell Line, Tumor
• B7 Antigens/metabolism

• B7-H3
• CAR-T
• bibliometric
• cancer immunotherapy
• trends

• Humans
• Bibliometrics
• Cluster Analysis
• Cross Reactions
• Immunotherapy/trends
• Neoplasms/therapy

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

Immunotherapy for cancer is a rapidly developing treatment that modifies the immune system and enhances the antitumor immune response. B7-H3 (CD276), a member of the B7 family that plays an immunoregulatory role in the T cell response, has been highlighted as a novel potential target for cancer immunotherapy. B7-H3 has been shown to play an inhibitory role in T cell activation and proliferation, participate in tumor immune evasion and influence both the immune response and tumor behavior through different signaling pathways. B7-H3 expression has been found to be aberrantly upregulated in many different cancer types, and an association between B7-H3 expression and poor prognosis has been established. Immunotherapy targeting B7-H3 through different approaches has been developing rapidly, and many ongoing clinical trials are exploring the safety and efficacy profiles of these therapies in cancer. In this review, we summarize the emerging research on the function and underlying pathways of B7-H3, the expression and roles of B7-H3 in different cancer types, and the advances in B7-H3-targeted therapy. Considering different tumor microenvironment characteristics and results from preclinical models to clinical practice, the research indicates that B7-H3 is a promising target for future immunotherapy, which might eventually contribute to an improvement in cancer immunotherapy that will benefit patients.

• B7-H3
• Biomarker
• Cancer immune checkpoints
• Cancer immunotherapy
• Tumor microenvironment

• Immune checkpoints
• Immunometabolism
• Liver cancer
• Natural killer cells

Hepatocellular carcinoma (HCC), the most common primary liver cancer has a high mortality in China, and it is usually diagnosed at a late stage, thereby leaving patients with few effective treatment options. Chimeric antigen receptor-T (CAR-T) cell therapy, a novel immunotherapy that has shown promising results in leukemia, lymphoma and multiple myeloma, is also expected to work well in solid tumors, including HCC. However, the ideal therapeutic efficacy has not yet been achieved, in part due to tumor antigen escape caused by antigen heterogeneity. To overcome such challenge, we screened a panel of biomarkers in HCC cell lines and found that GPC3 and B7H3 were highly expressed on HCC with expression heterogeneity. Then we developed a novel bispecific T cell engagers CAR-T (CAR.T-BiTEs) that drives the expression of a CAR specific for GPC3 and BiTEs against CD3 and B7H3, herein referred to as “GPC3-BiTE CAR.” We found that BiTEs promoted the increased activation of untransduced T cells and IFN-γ release. Moreover, BiTEs secreted by GPC3-BiTE CAR-HEK293T cells promoted increased cytotoxicity activity of untransduced T cells against GPC3+/B7H3+ (GPC3 positive/B7H3 positive) and GPC3-/B7H3+(GPC3 negative/B7H3 positive) HCC cell lines. In vitro function assays showed that GPC3-BiTE CAR-T cells exhibited greater cytotoxicity activity against GPC3+/B7H3+ HCC cell lines than GPC3 CAR-T cells (GPC3-targeted CAR-T cells) and B7H3 CAR-T cells (B7H3-targeted CAR-T cells). Furthermore, GPC3-BiTE CAR-T cells exhibited superior cytotoxicity against GPC3 negative HCC cell lines compared with GPC3 CAR T cells. In conclusion, our study showed that GPC3-BiTE CAR T cells exhibited superior antitumor activity than single-target CAR-T cells and can overcome tumor escape induced by antigen heterogeneity, suggesting that this could be a promising therapeutic strategy for HCC.

•

The expression of GPC3 and B7H3 was heterogeneous in HCC tissues.

• AC12-GGGC
• B7-H3
• SKOV-3 xenograft
• SPECT/CT imaging
• affibody molecule
• technetium-99m (99mTc)

• B7 homolog 3
• Gastric cancer
• Human epidermal growth receptor 2 gene
• Immunotherapy
• Trastuzumab

Small-cell lung cancer (SCLC) encounters up 15% of all lung cancers, and is characterized by a high rate of proliferation, a tendency for early metastasis and generally poor prognosis. Most of the patients present with distant metastatic disease at the time of clinical diagnosis, and only one-third are eligible for potentially curative treatment. Recently, investigations into the genomic make-up of SCLC show extensive chromosomal rearrangements, high mutational burden and loss-of-function mutations of several tumor suppressor genes. Although the clinical development of new treatments for SCLC has been limited in recent years, a better understanding of oncogenic driver alterations has found potential novel targets that might be suitable for therapeutic approaches. Currently, there are six types of potential treatable signaling pathways in SCLC, including signaling pathways targeting the cell cycle and DNA repair, tumor development, cell metabolism, epigenetic regulation, tumor immunity and angiogenesis. At this point, however, there is still a lack of understanding of their role in SCLC tumor biology and the promotion of cancer growth. Importantly optimizing drug targets, improving drug pharmacology, and identifying potential biomarkers are the main focus and further efforts are required to recognize patients who benefit most from novel therapies in development. This review will focus on the current learning on the signaling pathways, the status of immunotherapy, and targeted therapy in SCLC.

• B7-H3
• B7-H4
• HHLA2
• Multi-color immunohistochemistry
• Pancreatic cancer
• Prognosis

• Biomarkers, Tumor/metabolism
• Humans
• Immunoglobulins
• Immunohistochemistry
• Lymphocytes, Tumor-Infiltrating/pathology
• Pancreatic Neoplasms/pathology
• Prognosis
• Tumor Microenvironment
• Pancreatic Neoplasms

•

ALYREF is a potential prognostic marker for hepatocellular carcinoma.

Although ALYREF has been demonstrated to have a role in a number of malignancies, its role in hepatocellular carcinoma (HCC) has received little attention. Our objective was to research at the prognostic value, biological role and relevance of ALYREF to the immune system in HCC.

The expression of ALYREF and its relationship with clinical parameters of HCC patients were analyzed by liver cancer cohort (LIHC) of The Cancer Genome Atlas. The expression and prognosis were verified by immunohistochemistry experiments. Gene transfection, CCK-8, scratch healing, transwell invasion and flow cytometry were used to assess the molecular function of ALYREF in vitro. The TIMER and TISIDB online data portals were used to assess the relevance of ALYREF to immunization. Stepwise regression analysis of ALYREF-related immune genes in the LIHC training set was used to construct a prognostic risk prediction model. Also, construct a nomogram to predict patient survival. The testing set for internal verification.

Knockdown of ALYREF changed the biological phenotypes of HCC cells, such as proliferation, apoptosis, and invasion. In addition, the expression of ALYREF in HCC affected the level of immune cell infiltration and correlated with the overall survival time of patients. The constructed immune prognostic model allows for a valid assessment of patients.

ALYREF is increased in HCC, has an impact on cellular function and the immune system, and might be used as a prognostic marker.

• ALYREF
• HCC
• Immune
• Nomogram
• Prognosis

B7-H3 plays an important role in tumor apoptosis, proliferation, adhesion, angiogenesis, invasion, migration, and evasion of immune surveillance. It is overexpressed in various human solid tumor tissues. In patients, B7-H3 overexpression correlates with advanced stages, poor clinical outcomes, and resistance to therapy. The roles of B7-H3 in tumor progression make it a potential candidate for targeted therapy. Here, we generated a mouse anti-human B7-H3 antibody and demonstrated its binding activity via Tongji University Suzhou Instituteprotein-based and cell-based assays. We then developed a novel format anti-B7-H3 × anti-CD3 bispecific antibody based on the antibody-binding fragment of the anti-B7-H3 antibody and single-chain variable fragment structure of anti-CD3 antibody (OKT3) and demonstrated that this bispecific antibody mediated potent cytotoxic activities against various B7-H3-positive tumor cell lines in vitro by improving T cell activation and proliferation. This bispecific antibody also demonstrated potent antitumor activity in humanized mice xenograft models. These results revealed that the novel anti-B7-H3 × anti-CD3 bispecific antibody has the potential to be employed in treatment of B7-H3-positive solid tumors.

Upon transmission to the human host, Plasmodium sporozoites exit the skin, are taken up by the blood stream, and then travel to the liver where they infect and significantly modify a single hepatocyte. Low infection rates within the liver have made proteomic studies of infected hepatocytes challenging, particularly in vivo, and existing studies have been largely unable to consider how protein and phosphoprotein differences are altered at different spatial locations within the heterogeneous liver. Using digital spatial profiling, we characterized changes in host signaling during Plasmodium yoelii infection in vivo without disrupting the liver tissue. Moreover, we measured alterations in protein expression around infected hepatocytes and identified a subset of CD163⁺ Kupffer cells that migrate towards infected cells during infection. These data offer the first insight into the heterogeneous microenvironment that surrounds the infected hepatocyte and provide insights into how the parasite may alter its milieu to influence its survival and modulate immunity.

• Animals
• Humans
• Liver/parasitology
• Malaria/parasitology
• Plasmodium
• Proteomics
• Sporozoites

• T32 HD007233 NICHD NIH HHS
• R01 AI158719 NIAID NIH HHS
• National Institutes of Health

• tumour immunology
• cancer therapy
• immunotherapy

Hepatocellular carcinoma (HCC) is a common malignant tumor with relatively high malignancy and rapid disease progression. Metabolism-related genes (MRGs) are involved in the pathogenesis of HCC. This study explored potential key MRGs and their effect on T-cell immune function in the tumor immune microenvironment to provide new insight for the treatment of HCC. Of 456 differentially expressed MRGs identified from TCGA database, 21 were screened by MCODE and cytoHubba algorithms. From the key module, GAD1, SPP1, WFS1, GOT2, EHHADH, and APOA1 were selected for validation. The six MRGs were closely correlated with survival outcomes and clinicopathological characteristics in HCC. Receiver operating characteristics analysis and Kaplan-Meier plots showed that these genes had good prognostic value for HCC. Gene set enrichment analysis of the six MRGs indicated that they were associated with HCC development. TIMER and GEPIA databases revealed that WFS1 was significantly positively correlated and EHHADH was negatively correlated with tumor immune cell infiltration and immune checkpoint expression. Finally, quantificational real-time polymerase chain reaction (qRT-PCR) confirmed the expression of WFS1 and EHHADH mRNA in our own patients’ cohort samples and four HCC cell lines. Collectively, the present study identified six potential MRG biomarkers associated with the prognosis and tumor immune infiltration of HCC, thus providing new insight into the pathogenesis and treatment of HCC.

• hepatocellular carcinoma
• immune checkpoint
• metabolism‐related genes
• prognosis
• tumor infiltrating

• B7-H3
• Immunotherapy
• MicroRNA
• Tumor microenvironment
• Tumor progression

• B7 Antigens/genetics
• B7 Antigens/metabolism
• Cytokines/genetics
• Cytokines/metabolism
• Gene Expression Regulation/physiology
• Humans
• Macrophages
• T-Lymphocytes/physiology
• Tissue Distribution

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

• costimulatory and inhibitory T-cell receptors
• prostatic neoplasms
• tumor biomarkers
• tumor microenvironment

More than 70% of colorectal, prostate, ovarian, pancreatic and breast cancer specimens show expression of CD276 (B7–H3), a potential immune checkpoint family member. Several studies have shown that high CD276 expression in cancer cells correlates with a poor clinical prognosis. This has been associated with the presence of lower tumor infiltrating leukocytes. Among those, tumor-associated macrophages can comprise up to 50% of the tumor mass and are thought to support tumor growth through various mechanisms. However, a lack of information on CD276 function and interaction partner(s) impedes rigorous evaluation of CD276 as a therapeutic target in oncology. Therefore, we aimed to understand the relevance of CD276 in tumor-macrophage interaction by employing a 3D spheroid coculture system with human cells. Our data show a role for tumor-expressed CD276 on the macrophage recruitment into the tumor spheroid, and also in regulation of the extracellular matrix modulator PAI-1. Furthermore, our experiments focusing on macrophage-expressed CD276 suggest that the antibody-dependent CD276 engagement triggers predominantly inhibitory signaling networks in human macrophages.

• 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
• Gastric cancer
• Granulocyte-macrophage colony stimulating factor
• Neutrophils

Multiplex immunofluorescence (mIF) has arisen as an important tool for immuno-profiling tumor tissues. We updated our manual protocol into an automated protocol that allows the use of up to seven markers in five mIF panels to apply to formalin-fixed paraffin-embedded tumor tissues. Using a tyramide signal amplification system, we optimized five mIF panels that included cytokeratin to characterize malignant cells (MCs), immune checkpoint markers (i.e., PD-L1, B7-H3, B7-H4, IDO-1, VISTA, LAG3, ICOS, TIM3, and OX40), tumor-infiltrating lymphocytic markers (i.e., CD3, CD8, CD45RO, granzyme B, PD-1, and FOXP3), and markers to characterize myeloid-derived suppressor cells (i.e., CD68, CD66b, CD14, CD33, Arg-1, and CD11b). To determine analytical reproducibility and the impact of those panels for immuno-profiling tumor tissues, we performed an exploratory analysis in a set of non–small cell lung cancer (NSCLC) samples. The slides were scanned, and the different cell phenotypes were quantified by simultaneous co-localizations with the markers using image analysis software. Comparison between the time points of staining showed high analytical reproducibility. The analysis of NSCLC cases showed an immunosuppressive microenvironment with PD-L1/PD-1 expression as a predominant axis. Interestingly, high density of MCs expressing B7-H4 was correlated with recurrence. Unexpectedly, MCs expressing OX40 were also detected, and those cells were a closer distance to CD3+T-cells than were MCs expressing other immune checkpoints. Two different cellular patterns of spatial distribution were determined according the CD3 distribution, and the predominant pattern was related with active immunosuppressive interaction with MCs. Our study shows that these five mIF panels can identify multiple targets in a single cell with high reproducibility. The study of different cell populations and their spatial relationship can open new ideas for therapeutic approaches.

In recent years, immune checkpoint inhibitors have shown significant effects in a variety of solid tumors. However, due to the low incidence of small cell lung cancer (SCLC) and its unclear mechanism, immune checkpoints in SCLC have not been fully studied.

We evaluated the expression of PD-L1, B7-H3, and B7-H4 in 115 SCLC tissue specimens using immunohistochemistry. The clinical data of patients with SCLC were retrospectively reviewed to investigate three negative co-stimulatory B7 family molecules’ ability to affect the prognosis of SCLC.

Among the SCLC patients with complete follow-up data (n = 107), sixty-nine (64.49%) expressed moderate to high B7-H3 levels, which correlated positively with tumor sizes (P < 0.001). Eighty (74.77%) patients expressed moderate to high B7-H4 levels, which correlated positively with metastases (P = 0.049). The positive expression of B7-H3 and B7-H4 correlated significantly with shortened overall survival (OS) (B7-H3, P = 0.006; B7-H4, P = 0.019). PD-L1 was positively expressed only in 13.08% of cancer tissues, and there was no significant correlation with prognosis. The Cox proportional hazards regression showed that B7-H3 was an independent prognostic indicator of OS (P = 0.028; HR = 2.125 [95% CI = 0.985-4.462]).

Our results suggest that B7-H3 has a negative predictive effect on SCLC. This outcome provides a theoretical basis for the subsequent research on immune checkpoint inhibitors targeting B7-H3.

• B7-H3
• B7-H4
• PD-L1
• immune checkpoint
• immunity therapy
• small cell lung cancer

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

• CD276
• hepatocellular carcinoma
• matrix metalloproteinases
• vasculogenic mimicry

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

Mechanisms of dysfunctional T cell immunity in Hepatocellular Carcinoma (HCC) need to be well defined. B7 family molecules provide both co-stimulatory and co-inhibitory signals to T cells while tryptophan degrading enzymes like Indoleamine 2,3 dioxygenase (IDO) and Tryptophan 2,3 Dioxygenase (TDO) mediate tumor immune tolerance. It is necessary to identify their in situ correlative expression, which informs targets for combined immunotherapy approaches. We investigated B7 family molecules, IDO, TDO and immune responsive effectors in the tumor tissues of patients with HCC (n = 28) using a pathway-focused quantitative nanoscale chip real-time PCR. Four best correlative expressions, namely (1) B7-1 & PD-L2, (2) B7-H2 & B7-H3, (3) B7-2 & PD-L1, (4) PD-L1 & PD-L2, were identified among B7 family ligands, albeit they express at different levels. Although TDO expression is higher than IDO, PD-L1 correlates only with IDO but not TDO. Immune effector (Granzyme B) and suppressive (PD-1 and TGF-β) genes correlate with IDO and B7-1, B7-H5, PD-L2. Identification of the in situ correlation of PD-L1, PD-L2 and IDO suggest their cumulative immuno suppressive role in HCC. The distinct correlations among B7-1, B7-2, B7-H2, and B7-H3, correlation of PD-1 with non-cognate ligands such as B7-1 and B7-H5, and correlation of tumor lytic enzyme Granzyme B with IDO and PD-L2 suggest that HCC microenvironment is complexly orchestrated with both stimulatory and inhibitory molecules which together neutralize and blunt anti-HCC immunity. Functional assays demonstrate that both PDL-1 and IDO synergistically inhibit T cell responses. Altogether, the present data suggest the usage of combined immune checkpoint blocking strategies targeting co-inhibitory B7 molecules and IDO for HCC management.

• B7 family molecules
• PD-L1
• T cell immunity
• co-inhibition
• co-stimulation
• hepatocellular carcinoma
• indoleamine 2,3 dioxygenase

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

• Adult cancers
• Clinical trials
• Immune checkpoint inhibitors
• Immunotherapy
• Pediatric cancers

Recent studies demonstrate that immune checkpoint inhibitor (ICI) therapy has achieved success in many types of advanced cancers including advanced hepatocellular carcinoma (HCC). However, ICI therapy is beneficial in only some HCC patients, suggesting that immune-responses are highly variable in HCCs. Therefore, understanding the immune status in HCC microenvironment will facilitate ICI immunotherapy and guide patient selection for the therapy. In this study, we first analyzed the expression profile of immune-modulating genes and their relationship with survival of HCC patients using the data downloaded from The Cancer Genome Atlas - Liver Hepatocellular Carcinoma (TCGA-LIHC) database, and found that the higher expressions of CD276 (B7-H3) and CD47 were significantly associated with poor survival. Then we identified 4 immune subtypes of HCCs with different survivals by using the combination expression of B7-H3 (or CD47) and CD8. Patients with B7-H3^low/CD8^high or CD47^low/CD8^high have the best survival while ones with B7-H3^high/CD8^low or CD47^high/CD8^low have the worst survival. The 4 immune subtypes were validated in another 72 HCC patients obtained from South China. In conclusion, our findings suggest that HCC patient prognosis is associated with immunophenotypes by T cell infiltration (CD8 expression) and the expression of the adaptive immune resistance gene (B7-H3 or CD47), and this immune classification system will facilitate HCC patient selection for ICI immunotherapy.

• B7-H3
• CD47
• CD8
• hepatocellular carcinoma
• immune checkpoint

• B7-H3
• Immune checkpoint
• Non–small-cell lung cancer
• Tumour microenvironment
• Tumour-infiltrating immune cells

Neuroblastoma (NB) is a malignant embryonal tumor of the sympathetic nervous system that is most commonly diagnosed in the abdomen, often presenting with signs and symptoms of metastatic spread. Three decades ago, high-risk NB metastatic to bone and bone marrow in children was not curable. Today, with multimodality treatment, 50% of these patients will survive, but most suffer from debilitating treatment-related complications. Novel targeted therapies to improve cure rates while minimizing toxicities are urgently needed. Recent molecular discoveries in oncology have spawned the development of an impressive array of targeted therapies for adult cancers, yet the paucity of recurrent somatic mutations or activated oncogenes in pediatric cancers poses a major challenge to the evolving paradigm of personalized medicine. Although low tumor mutational burden is a major hurdle for immune checkpoint inhibitors, an immature or impaired immune system and inhibitory tumor microenvironment can further complicate the prospects for successful immunotherapy. In this regard, despite the poor immunogenic properties of NB, the success of antibody-based immunotherapy and radioimmunotherapy directed at single targets (eg, GD2 and B7-H3) is both encouraging and surprising, given that most solid tumor antibodies that use Fc-dependent mechanisms or radioimmunotargeting have largely failed. Here, we summarize the current information on the immunologic properties of this tumor, its potential immunotherapeutic targets, and novel antibody-based strategies on the horizon.

Background: B7-H3 promotes tumor immune escape and is highly expressed in tumor tissues. Stromal cells in tumors, including fibroblasts, play an important role in this process; however, the role of B7-H3 in tumor fibroblasts has not been fully clarified.

Methods: We examined B7-H3, CD31, and alpha-smooth muscle actin (α-SMA) protein expression in 268 gastric adenocarcinomas (GACs) by immunohistochemistry. The coexpression of B7-H3 with CD31 or α-SMA was examined using immunofluorescence double staining. Cytokine expression from fibroblasts treated with B7-H3 small interfering RNA (siRNA) was analyzed by a Quantitative reverse transcription-polymerase chain reaction (qPCR) and Enzyme-linked immunosorbent assay (ELISA). The transwell tests were conducted to assess the migration and invasion ability of fibroblasts. The overall survival was analyzed by a Kaplan-Meier analysis. Associations between categorical variables were assessed using the Pearson's Chi-square test or Fisher's exact test.

Results: GAC patients with B7-H3 expression showed significantly poorer survival (P = 0.012). The overall survival of the group with high B7-H3 expression was significantly worse than the group with low B7-H3 expression in both tumor cells and in stromal cells (P = 0.007 and P = 0.048, respectively). B7-H3 expression correlated with many clinicopathological data, including tumor stage, tumor depth, lymph node involvement, and survival. Immunofluorescence staining showed that B7-H3 was expressed in tumor cells and α-SMA-positive fibroblasts. Remarkably, high expression of α-SMA was associated with a poor prognosis (P = 0.007), and the prognoses of patients with high stromal expression of B7-H3 and α-SMA were significantly worse than that of other combination types (P = 0.001). Additionally, the absence of B7-H3 led to decreased secretion of cytokines, such as interleukin (IL)-6 and vascular endothelial growth factor (VEGF), as well as a decline in migration and invasion ability in cancer-associated fibroblasts (CAFs).

Conclusions: Patients with high B7-H3 expression either in tumor cells or in stromal cells had significantly poorer overall survival. Stromal B7-H3 expression was mostly detected in α-SMA-positive CAFs. GAC patients with both stromal B7-H3-high and α-SMA-high expression had significantly poorer overall survival, suggesting that stromal B7-H3 and α-SMA expression status can serve as an indicator of poor prognosis for GAC patients.

• B7-H3
• cancer-associated fibroblast
• gastric adenocarcinoma
• prognosis
• α-SMA

• CTLA-4
• Immunotherapy
• PD-1
• T cells
• checkpoint blockade
• resistance.

Liver transplantation is an effective therapy for end‐stage liver diseases and acute liver failure. After the operation, however, recipients may suffer grafts loss induced by alloimmune reaction, which is termed as acute allograft rejection. The interaction between costimulatory molecules, CD276, and its ligand, TREML2, promotes T cell‐mediated immune response, as well as acute or chronic allograft rejection. Our research aimed at correlating genetic polymorphisms of CD276/TREML2 with acute rejection, and evaluating its prognostic value of acute rejection after liver transplantation.

The study enrolled a total of 388 recipients. Among them, acute allograft rejection was observed in 54 cases. We performed single nucleotide polymorphism genotyping of CD276, including rs11072431, rs11574495, rs12593558, rs12594627, rs2127015, rs3816661 and rs7176654, and TREML2, including rs4714431, rs6915083, rs7754593, and rs9394767 from preoperative peripheral blood genome DNA.

We found rs2127015 of CD276, rs6915083 and rs7754593 of TREML2, and HBV infection as well were associated with acute rejection. And, rs2127015 influences CD276 expression. Moreover, we established a risk assessment model, composited by statistically proved risk factors.

By integrating both clinical and genetic variables, liver transplant recipients can be categorized into different risk groups, and might benefit from individualized therapies.

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