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MTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion

ABSTRACT: mTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion

PROVIDER: PRJNA883227 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21622525.fastq.gz	Fastqsanger.gz
	SRR21622526.fastq.gz	Fastqsanger.gz
	SRR21622527.fastq.gz	Fastqsanger.gz
	SRR21622528.fastq.gz	Fastqsanger.gz
	SRR21622529.fastq.gz	Fastqsanger.gz

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

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

| PRJNA883235 | ENA

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

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

| PRJNA881954 | ENA

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

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

RNA sequencing analysis for mouse ovarian cancer cells and tumors response to B7-H3 (Cd276) depletion

Project description:Analysis of mouse ovarian cancer cell lines HM-1 and ID8, and HM-1 tumors inoculated to B6C3F1 mice with B7-H3 (Cd276) knockout (KO) by CRISPR-Cas9. We identified B7-H3 expression is upregulated in IFN-γ–low, PD-L1–low non-immunoreactive tumors of high grade serous ovarian cancer. We explored the influence of B7-H3 on immune evasion outside of its direct regulatory function on target cells by generating B7-H3 knockout cell lines and tumors in syngeneic mouse models.

2022-01-10 | GSE174137 | GEO

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-02-09 | GSE213941 | GEO

A Dual-Payload Antibody-Drug Conjugate Targeting CD276/B7-H3 Elicits Cytotoxicity and Immune Activation in Triple-Negative Breast Cancer

Project description:Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous disease that often relapses following treatment with standard radiotherapies and cytotoxic chemotherapies. Combination therapies have potential for treating refractory metastatic TNBC. Here, we aimed to develop an antibody-drug conjugate with dual payloads (DualADC) as a chemo-immunotherapy for TNBC. The overexpression of an immune checkpoint transmembrane CD276 (also known as B7-H3) was associated with angiogenesis, metastasis, and immune tolerance, in over 60% of TNBC patients. Development of a monoclonal antibody (mAb) capable of targeting the extracellular domain of surface CD276 enabled delivery of payloads to tumors, and a platform was established for concurrent conjugation of a traditional cytotoxic payload and an immunoregulating toll-like receptor 7/8 agonist to the CD276 mAb. The DualADC effectively killed multiple TNBC subtypes, significantly enhanced immune functions in the tumor microenvironment, and reduced tumor burden by up to 90-100% in animal studies. Single-cell RNA-sequencing, multiplex cytokine analysis, and histology elucidated the impact of treatment on tumor cells and the immune landscape. This study suggests that the developed DualADC could represent a promising targeted chemo-immunotherapy for TNBC.

2024-08-21 | GSE274871 | GEO

CD276 is an important player in macrophage recruitment into the tumor and an upstream regulator for PAI-1

Project description:70-100% 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.

2021-07-28 | GSE165610 | GEO

Targeting Osteosarcoma with Canine B7-H3 CAR T Cells and Impact of CXCR2 Co-Expression on Functional Activity

Project description:Abstract. 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. Therefore, 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 and glioma 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 high levels of B7-H3, whereas levels were undetectable on normal dog tissues. In vitro, 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 antitumor 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.

2024-04-03 | GSE247355 | GEO

RNA sequencing analysis for mouse ovarian cancer cells and tumors response to B7-H3 (Cd276) depletion

Project description:RNA sequencing analysis for mouse ovarian cancer cells and tumors response to B7-H3 (Cd276) depletion

| PRJNA728566 | ENA