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Combined blockade of B7-H3 and CD47 immune checkpoints is a new therapeutic strategy for β-catenin driven melanomas [YUMMER1.7]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE161177 | GEO | 2023/10/30

REPOSITORIES: GEO

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Combined blockade of B7-H3 and CD47 immune checkpoints is a new therapeutic strategy for β-catenin driven melanomas [YUMM 2.1]

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

Combined blockade of B7-H3 and CD47 immune checkpoints is a new therapeutic strategy for β-catenin driven melanomas [transfection]

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

Combined blockade of B7-H3 and CD47 immune checkpoints is a new therapeutic strategy for β-catenin driven melanomas [I]

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

Combined blockade of B7-H3 and CD47 immune checkpoints is a new therapeutic strategy for β-catenin driven melanomas [single cell CD45+ YUMM 2.1]

2023-10-30 | GSE186382 | GEO

mTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion [CITE-Seq]

Project description:Immune checkpoints are often expressed on tumor cells; it remains a prevailing need to identify the mechanisms underlying their regulation and therapeutic benefit. The immune checkpoint molecule B7-H3 is upregulated in many human tumors, including those with high mechanistic/mammalian target of rapamycin complex (mTORC1) activity. However, its role in tumor immunity and the impact of B7-H3-targeted therapy on the tumor immune microenvironment are largely uncharacterized. Here, we used a syngeneic murine model of tuberous sclerosis complex (TSC), a model of mTORC1 hyperactivity, to assess the mechanisms by which B7-H3 remodels the tumor microenvironment. We performed gene and protein expression profiling analysis using data generated from CITE-seq of infiltrating CD3+ T cells isolated by FACS from subcutaneous B7-H3 knockdown and control TSC2-deficient 105K tumors.

2023-02-08 | GSE213939 | GEO

mTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion [RNA-seq]

Project description:Immune checkpoints are often expressed on tumor cells; it remains a prevailing need to identify the mechanisms underlying their regulation and therapeutic benefit. The immune checkpoint molecule B7-H3 is upregulated in many human tumors, including those with high mechanistic/mammalian target of rapamycin complex (mTORC1) activity. Still, its role in tumor immunity and the impact of B7-H3-targeted therapy on the tumor immune microenvironment are largely uncharacterized in mTORC1-hyperactive tumors. Here, we used a syngeneic murine model of tuberous sclerosis complex (TSC), a model of mTORC1 hyperactivity, to assess the mechanisms by which B7-H3 remodels the tumor microenvironment. We performed gene expression profiling analysis using data generated from RNA-seq of bulk tumors from subcutaneous B7-H3 knockdown and control TSC2-deficient 105K cells or sorted tumor cells isolated by MACS mouse tumor cell isolation kit (Miltenyi Biotec).

2023-02-08 | GSE213626 | GEO

Mouse melanoma types with various genotypes

Project description:Only a subset of melanoma patients has evidence for spontaneous T cell infiltration into tumor sites, previously associated with clinical responses. However, the molecular mechanisms explaining absence of a T cell response are not yet defined. Analyses of human melanoma metastases have revealed that T cell signature low tumors show alterations in the Wnt/b-catenin signaling pathway. We utilized an inducible mouse model driven by inducible BrafV600E and PTEN-deletion, with or without active b-catenin (CAT-STA) to test if tumor intrinsic active b-catenin can block anti-tumor immunity. While Braf/PTEN melanomas showed presence of a T cell infiltrate, T cells were nearly completely eliminated in tumors expressing active b-catenin. Adoptive transfer experiments revealed defective T cell priming when tumors expressed active b-catenin. Analysis of the antigen-presenting cell compartment revealed a selective decrease in the CD103+ DC subset within the tumor microenvironment, which could be associated with b-catenin depended inhibition of expression of the chemokine CCL4 within tumor cells. Here we used 3 mice of each genotype BrafV600E/PTEN-/- and BrafV600E/PTEN-/-/Cat-STA and compared their gene-expression profiles. we used 3 mice of each genotype BrafV600E/PTEN-/- and BrafV600E/PTEN-/-/Cat-STA and compared their gene-expression profiles.

2015-02-28 | E-GEOD-63543 | biostudies-arrayexpress

CD47 in the tumor microenvironment and CD47 antibody blockade regulate natural killer cell recruitment and activation

Project description:Elevated CD47 expression in some cancers is associated with decreased survival and limits phagocytic clearance by engaging its counter-receptor SIRPα, but elevated CD47 mRNA expression in human melanomas is associated with improved survival. Gene expression data suggested that recruitment of natural killer (NK) cells, which highly express CD47, into the tumor microenvironment contribute to this correlation. The CD47 ligand thrombospondin-1 inhibited wildtype but not Cd47-/- murine NK cell proliferation and granzyme B and interferon-γ expression in vitro. Cd47-/- NK cells correspondingly showed augmented effector phenotypes. Although, wildtype and Cd47-/- NK cells were equally effective for killing B16 melanoma cells in vitro, Cd47-/- mice exhibited enhanced B16 tumor growth in vivo. Consistent with the human data, tumor-bearing Cd47-/- mice had decreased splenic NK numbers with impaired effector protein expression and elevated exhaustion markers. A pro-apoptotic signature in Cd47-/- NK cells was associated with stress-mediated elevation of mitochondrial proton leak, increased reactive oxygen species and apoptosis. Gene expression profiling identified CD47-dependent transcriptional responses in in NK cells from tumor-bearing mice that regulate systemic NK activation and exhaustion. Treating wildtype mice with a CD47 antibody that blocks thrombospondin-1 binding delayed tumor growth and was associated with increased NK recruitment and increased granzyme B- and interferon-γ levels in intratumoral NK but not CD8+ T cells. Therefore, CD47 in the tumor microenvironment regulates NK-mediated tumor immunity, and therapeutic blockade enhances NK immune function.

2020-04-13 | GSE113876 | GEO

Effects of itaconate on gene expression in mouse CD8 T cells

Project description:The tumor microenvironment possesses multiple overlapping mechanisms that suppress anti-tumor immunity. Itaconate is a metabolite produced from the Krebs cycle intermediate cis-aconitate by the activity of immune-responsive gene 1 (IRG1). While it is known to be immune modulatory, the role of itaconate in anti-tumor immunity is unclear. Here, we demonstrate that myeloid-derived suppressor cells (MDSCs) secreted itaconate that can be taken up by CD8+ T cells and suppress their proliferation, cytokine production, and cytolytic activity. Metabolite profiling, stable-isotope tracing and metabolite supplementation studies indicated that itaconate suppressed biosynthesis of aspartate and serine/glycine in CD8+ T cells to attenuate their proliferation. Moreover, stromal deletion of IRG1 in mice bearing allografted tumors resulted in decreased tumor growth, inhibited the immune suppressive activities of MDSCs, reduced levels of itaconate in tumors, promoted anti-tumor immunity of CD8+ T cells, and enhanced the anti-tumor activity of anti-PD-1 antibody treatment. Importantly, we found a significant negative correlation between IRG1 expression and response to PD-1 immune checkpoint blockade in melanoma patients. Our findings not only reveal a previously unknown role of itaconate as an immune checkpoint metabolite secreted from MDSCs to suppress CD8+ T cells, but also establish IRG1 as a novel myeloid-selective target in immunometabolism to promote anti-tumor immunity and enhance the efficacy of immune checkpoint protein blockade.

2022-11-15 | GSE190028 | GEO

Immunologic and clinical activity to ICB combinations in DAPPER Leiomyosarcoma cohort

Project description:Non-inflamed (cold) tumors such as leiomyosarcoma (LMS) do not benefit from immune checkpoint blockade (ICB) monotherapy. Combining ICB with angiogenesis-, or poly-ADP ribose polymerase (PARP) inhibitors may increase tumor immunogenicity by altering the immune cell composition of the tumor microenvironment (TME). The DAPPER phase II study evaluated the safety, immunologic, and clinical activity of ICB-based combinations in pre-treated LMS patients.

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