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Project description:In melanoma, immune cell infiltration into the tumor is associated with better patient outcomes and response to immunotherapy. T cell non-inflamed tumors (‘cold tumors’) are associated with tumor cell intrinsic Wnt/β-catenin activation, and are resistant to anti-PD-1 alone or in combination with anti-CTLA-4 therapy. Reversal of the ‘cold tumor’ phenotype and identifying new effective immunotherapies are challenges in melanoma. In a well-established preclinical melanoma model driven by β-catenin, we found that immune checkpoint molecule B7-H3 confers a suppressive tumor microenvironment by modulating antiviral signals and matricellular proteins. Its inhibition primes the microenvironment, and together with blockade of the macrophage checkpoint CD47, but not with anti-PD-1, results in synergistic anti-tumor responses. This study brings B7-H3 to the forefront as inducing a suppressive microenvironment when overexpressed, and it’s co-targeting with CD47 as a novel combination of immune checkpoint inhibitors in melanoma that calls for testing in clinical trials.
2023-10-30 | GSE161177 | GEO
Project description:In melanoma, immune cell infiltration into the tumor is associated with better patient outcomes and response to immunotherapy. T cell non-inflamed tumors (‘cold tumors’) are associated with tumor cell intrinsic Wnt/β-catenin activation, and are resistant to anti-PD-1 alone or in combination with anti-CTLA-4 therapy. Reversal of the ‘cold tumor’ phenotype and identifying new effective immunotherapies are challenges in melanoma. In a well-established preclinical melanoma model driven by β-catenin, we found that immune checkpoint molecule B7-H3 confers a suppressive tumor microenvironment by modulating antiviral signals and matricellular proteins. Its inhibition primes the microenvironment, and together with blockade of the macrophage checkpoint CD47, but not with anti-PD-1, results in synergistic anti-tumor responses. This study brings B7-H3 to the forefront as inducing a suppressive microenvironment when overexpressed, and co-targeting with CD47 as a novel combination of immune checkpoint inhibitors in melanoma that calls for testing in clinical trials.
2023-10-30 | GSE155394 | GEO
Project description:In melanoma, immune cell infiltration into the tumor is associated with better patient outcomes and response to immunotherapy. T cell non-inflamed tumors (‘cold tumors’) are associated with tumor cell intrinsic Wnt/β-catenin activation, and are resistant to anti-PD-1 alone or in combination with anti-CTLA-4 therapy. Reversal of the ‘cold tumor’ phenotype and identifying new effective immunotherapies are challenges in melanoma. In a well-established preclinical melanoma model driven by β-catenin, we found that immune checkpoint molecule B7-H3 confers a suppressive tumor microenvironment by modulating antiviral signals and matricellular proteins. Its inhibition primes the microenvironment, and together with blockade of the macrophage checkpoint CD47, but not with anti-PD-1, results in synergistic anti-tumor responses. This study brings B7-H3 to the forefront as inducing a suppressive microenvironment when overexpressed, and co-targeting with CD47 as a novel combination of immune checkpoint inhibitors in melanoma that calls for testing in clinical trials.
2023-10-30 | GSE155386 | GEO
Project description:In melanoma, immune cell infiltration into the tumor is associated with better patient outcomes and response to immunotherapy. T cell non-inflamed tumors (‘cold tumors’) are associated with tumor cell intrinsic Wnt/β-catenin activation, and are resistant to anti-PD-1 alone or in combination with anti-CTLA-4 therapy. Reversal of the ‘cold tumor’ phenotype and identifying new effective immunotherapies are challenges in melanoma. In a well-established preclinical melanoma model driven by β-catenin, we found that immune checkpoint molecule B7-H3 confers a suppressive tumor microenvironment by modulating antiviral signals and matricellular proteins. Its inhibition primes the microenvironment, and together with blockade of the macrophage checkpoint CD47, but not with anti-PD-1, results in synergistic anti-tumor responses. This study brings B7-H3 to the forefront as inducing a suppressive microenvironment when overexpressed, and it’s co-targeting with CD47 as a novel combination of immune checkpoint inhibitors in melanoma that calls for testing in clinical trials.
2023-10-30 | GSE161178 | GEO
Project description:In melanoma, immune cell infiltration into the tumor is associated with better patient outcomes and response to immunotherapy. T cell non-inflamed tumors (‘cold tumors’) are associated with tumor cell intrinsic Wnt/β-catenin activation, and are resistant to anti-PD-1 alone or in combination with anti-CTLA-4 therapy. Reversal of the ‘cold tumor’ phenotype and identifying new effective immunotherapies are challenges in melanoma. In a well-established preclinical melanoma model driven by β-catenin, we found that immune checkpoint molecule B7-H3 confers a suppressive tumor microenvironment by modulating antiviral signals and matricellular proteins. Its inhibition primes the microenvironment, and together with blockade of the macrophage checkpoint CD47, but not with anti-PD-1, results in synergistic anti-tumor responses. This study brings B7-H3 to the forefront as inducing a suppressive microenvironment when overexpressed, and it’s co-targeting with CD47 as a novel combination of immune checkpoint inhibitors in melanoma that calls for testing in clinical trials.
2023-10-30 | GSE186382 | GEO
Project description:T cell activity is controlled by a combination of antigen-dependent signaling through the T cell receptor and a set of auxiliary signals delivered through antigen-independent interactions, including the recognition of the B7 family of ligands. B7-H3 is a recently identified B7 family member that is strongly overexpressed in a range of cancers and correlates with poor prognosis. We report the crystal structure of murine B7-H3 at a 3 Å resolution, which provides a model for the organization of the IgV and IgC domains within the ectodomain. We demonstrate that B7-H3 inhibits T cell proliferation and show that the FG loop of the IgV domain plays a critical role in this function. B7-H3 crystallized as an unusual dimer arising from the exchange of the G strands in the IgV domains of partner molecules. This arrangement, in combination with previous reports, highlights the dynamic nature and plasticity of the immunoglobulin fold.
| S-EPMC3998375 | biostudies-literature
Project description:B7-H3 belongs to the B7 superfamily, a group of molecules that costimulate or down-modulate T-cell responses. Although it was shown that B7-H3 could inhibit T-cell responses, several studies - most of them performed in murine systems - found B7-H3 to act in a costimulatory manner. In this study, we have specifically addressed a potential functional dualism of human B7-H3 by assessing the effect of this molecule under varying experimental conditions as well as on different T-cell subsets. We show that B7-H3 does not costimulate human T cells. In the presence of strong activating signals, B7-H3 potently and consistently down-modulated human T-cell responses. This inhibitory effect was evident when analysing proliferation and cytokine production and affected naïve as well as pre-activated T cells. Furthermore, we demonstrate that B7-H3-T-cell interaction is characterised by an early suppression of IL-2 and that T-cell inhibition can be reverted by exogenous IL-2. Since the triggering receptor expressed on myeloid cells like transcript 2 (TREML2/TLT-2) has been recently described as costimulatory receptor of murine B7-H3 we have extensively analysed interaction of human B7-H3 with TREML2/TLT-2. In these experiments we found no evidence for such an interaction. Furthermore, our data do not point to a role for murine TREML2 as a receptor for murine B7-H3.
| S-EPMC2978551 | biostudies-literature
Project description:Immunotherapy aiming at suppressing tumor development by relying on modifying or strengthening the immune system prevails among cancer treatments and points out a new direction for cancer therapy. B7 homolog 3 protein (B7-H3, also known as CD276), a newly identified immunoregulatory protein member of the B7 family, is an attractive and promising target for cancer immunotherapy because it is overexpressed in tumor tissues while showing limited expression in normal tissues and participating in tumor microenvironment (TME) shaping and development. Thus far, numerous B7-H3-based immunotherapy strategies have demonstrated potent antitumor activity and acceptable safety profiles in preclinical models. Herein, we present the expression and biological function of B7-H3 in distinct cancer and normal cells, as well as B7-H3-mediated signal pathways in cancer cells and B7-H3-based tumor immunotherapy strategies. This review provides a comprehensive overview that encompasses B7-H3's role in TME to its potential as a target in cancer immunotherapy.
| S-EPMC8326801 | biostudies-literature
Project description:BackgroundTargeted Radioimmunotherapy (RIT) is an attractive approach to selectively localize therapeutic radionuclides to malignant cells within primary and metastatic tumors while sparing normal tissues from the effects of radiation. Many human malignancies express B7-H3 on the tumor cell surface, while expression on the majority of normal tissues is limited, presenting B7-H3 as a candidate target for RIT. This review provides an overview of the general principles of targeted RIT and discusses publications that have used radiolabeled B7-H3-targeted antibodies for RIT of cancer in preclinical or clinical studies.MethodsDatabases including PubMed, Scopus, and Google Scholar were searched for publications through June 2018 using a combination of terms including "B7-H3", "radioimmunotherapy", "targeted", "radiotherapy", and "cancer". After screening search results for relevancy, ten publications were included for discussion.ResultsB7-H3-targeted RIT studies to date range from antibody development and assessment of novel Radioimmunoconjugates (RICs) in animal models of human cancer to phase II/III trials in humans. The majority of clinical studies have used B7-H3-targeted RICs for intra- compartment RIT of central nervous system malignancies. The results of these studies have indicated high tolerability and favorable efficacy outcomes, supporting further assessment of B7-H3-targeted RIT in larger trials. Preclinical B7-H3-targeted RIT studies have also shown encouraging therapeutic outcomes in a variety of solid malignancies.ConclusionB7-H3-targeted RIT studies over the last 15 years have demonstrated feasibility for clinical development and support future assessment in a broader array of human malignancies. Future directions worthy of exploration include strategies that combine B7-H3- targeted RIT with chemotherapy or immunotherapy.
| S-EPMC8668195 | biostudies-literature
Project description:BACKGROUND:The purpose of this study was to validate B7-H3 as a new cancer-specific endothelial marker in clear cell renal cell carcinoma. METHODS:B7-H3 expression patterns were compared between cancer and paired adjacent normal renal parenchyma by immunohistochemistry in paraffin-embedded specimens from 200 consecutive patients with clear cell renal cell carcinoma from January to December 2010. Four corpus luteum specimens were used as physiologic angiogenesis controls. B7-H3 messenger (m)RNA levels representing circulating endothelial cells were analyzed in 24 peripheral blood samples using real-time polymerase chain reaction. Collection and processing of tissue and peripheral blood samples was performed in compliance with the Declaration of Helsinki. RESULTS:Cancer cell-specific expression of B7-H3 was detected in 19% of clear cell renal cell carcinoma specimens, and tumor vasculature B7-H3 expression was confirmed in 98% (196) of cases. A diffuse pattern of vascular B7-H3 expression was associated with multiple adverse clinical and pathologic features (P<0.001). B7-H3 expression was not detected in paired adjacent normal renal parenchyma or vessels, or in luteal blood vessels. The B7-H3 mRNA level of circulating endothelial cells in peripheral blood was significantly higher in metastatic clear cell renal cell carcinoma (P<0.001). CONCLUSION:This pilot study indicates that B7-H3 is a cancer-specific endothelial marker of potential importance for the development of tumor-specific, vascular-targeted therapies, and is a prognostic marker in clear cell renal cell carcinoma.
| S-EPMC3833620 | biostudies-literature