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Fc-optimized CD40 Agonistic Antibody Induces Tertiary Lymphoid Structures and Systemic Antitumor Immunity in Metastatic Cancer Patients

ABSTRACT: These studies were performed to understand the transcriptional profile of immune cells following treatment with 2141-V11, the main comparison was injected tumors versus non-injected ones. In summary: hCD40/hFcγR mice were inoculated bilaterally with E0771 tumors (5*105). IT 2141-V11 or isotype-matched control Abs were given into one tumor (the largest of the two) on days 14 and 17. Both tumors were excised on day 18 for scRNAseq and TCR-seq of CD45+ cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE298036 | GEO | 2025/05/28

REPOSITORIES: GEO

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Fc-optimized CD40 Agonistic Antibody Induces Tertiary Lymphoid Structures and Systemic Antitumor Immunity in Metastatic Cancer Patients [Human]

Project description:Human peripheral blood mononuclear cells (PBMC) from participants of the clinical study were isolated and thawed using prewarmed BD BSA stain buffer (BD Biosciences), washed twice with ice-cold buffer and counted and CD45+ cells were sorted for RNA sequencing.

2025-05-28 | GSE298047 | GEO

Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma.

Project description:Gliomas are brain tumors characterized by an immunosuppressive microenvironment. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors, but are yet to be evaluated for glioma. Here, we demonstrate that systemic delivery of αCD40 in preclinical glioma models induces the formation of tertiary lymphoid structures (TLS) in proximity of meningeal tissue. In treatment-naïve glioma patients, the presence of TLS correlates with increased T cell infiltration. However, systemic delivery of αCD40 induces hypofunctional T cells and impairs the response to immune checkpoint inhibitors in pre-clinical glioma models. This is associated with a systemic induction of suppressive CD11b+ B cells post-αCD40 treatment, which accumulate in the tumor microenvironment. Our work unveils the pleiotropic effects of αCD40 therapy in glioma and reveals that immunotherapies can modulate TLS formation in the brain, opening up for future opportunities to regulate the immune response.

| S-EPMC8257767 | biostudies-literature

Agonistic CD40 Antibodies in Cancer Treatment.

Project description:CD40 is expressed on a variety of antigen-presenting cells. Stimulation of CD40 results in inflammation by upregulation of other costimulatory molecules, increased antigen presentation, maturation (licensing) of dendritic cells, and activation of CD8+ T cells. Here we analyzed gene expression data from The Cancer Genome Atlas in melanoma, renal cell carcinoma, and pancreatic adenocarcinoma and found correlations between CD40 and several genes involved in antigen presentation and T cell function, supporting further exploration of CD40 agonists to treat cancer. Agonist CD40 antibodies have induced anti-tumor effects in several tumor models and the effect has been more pronounced when used in combination with other treatments (immune checkpoint inhibition, chemotherapy, and colony-stimulating factor 1 receptor inhibition). The reduction in tumor growth and ability to reprogram the tumor microenvironment in preclinical models lays the foundation for clinical development of agonistic CD40 antibodies (APX005M, ChiLob7/4, ADC-1013, SEA-CD40, selicrelumab, and CDX-1140) that are currently being evaluated in early phase clinical trials. In this article, we focus on CD40 expression and immunity in cancer, agonistic human CD40 antibodies, and their pre-clinical and clinical development. With the broad pro-inflammatory effects of CD40 and its ligand on dendritic cells and macrophages, and downstream B and T cell activation, agonists of this pathway may enhance the anti-tumor activity of other systemic therapies.

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DDR1 plays a distinctive role in mammary tumour growth

Project description:Purpose: The goals of this study are to compare mammary tumor transcriptome profiling with or without DDR1 in immunocompetent mice in an unbiased way. Methods: In vitro samples: DDR1 WT or KO in vitro cultured E0771 cells were sequenced. Rag1-/- samples: DDR1 WT or KO E0771 cells were injected in Rag1-/- mice, and tumors were harvested and sequenced. C57BL/6 samples: DDR1 WT or KO E0771 cells were firstly inoculated into Rag1-/- mice. When tumor volume reached approximately 200~300 mm3 (usually 20 days after inoculation), 60 mg of tumor organoid were transplanted to WT C57BL/6 mice. Tumor samples were collected on day 4 after transplantation for RNA-seq. Antibody treatment samples: DDR1 KO E0771 cells were reconstituted with human DDR1, then injected into C57BL/6 mice. Isotype control IgG or anti-hDDR1 ECD antibody treatment (10mg/kg intrutumural) started when tumor volume reached approximately 100 mm3. Tumor samples were collected on day 6 after treatment for RNA-seq. Results: Approximately 50 million sequence reads were obtained per sample and identified more than 20,000 transcript isoforms. Conclusions: The RNA-seq results represents the detailed analysis of DDR1 WT/KO mammary tumor transcriptomes in immunocompetent mice C57BL/6.

2021-09-07 | GSE139239 | GEO

Fc-optimized CD40 Agonistic Antibody Induces Tertiary Lymphoid Structures and Systemic Antitumor Immunity in Metastatic Cancer Patients

Project description:Fc-optimized CD40 Agonistic Antibody Induces Tertiary Lymphoid Structures and Systemic Antitumor Immunity in Metastatic Cancer Patients

| PRJNA1267139 | ENA

Concepts for agonistic targeting of CD40 in immuno-oncology.

Project description:TNF Receptor Superfamily (TNF-R-SF) signaling is a structurally well-defined event that requires proper receptor clustering and trimerization. While the TNF-SF ligands naturally exist as trivalent functional units, the receptors are usually separated on the cell surface. Critically, receptor assembly into functional trimeric signaling complexes occurs through binding of the natural ligand unit. TNF-R-SF members, including CD40, have been key immunotherapeutic targets for over 20 years. CD40, expressed by antigen-presenting cells, endothelial cells, and many tumors, plays a fundamental role in connecting innate and adaptive immunity. The multiple investigated strategies to induce CD40 signaling can be broadly grouped into antibody-based or CD40L-based approaches. Currently, seven different antibodies and one CD40L-based hexavalent fusion protein are in active clinical trials. In this review, we describe the biology and structural properties of CD40, requirements for agonistic signal transduction through CD40 and summarize current attempts to exploit the CD40 signaling pathway for the treatment of cancer.

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Fc-optimized CD40 Agonistic Antibody Induces Tertiary Lymphoid Structures and Systemic Antitumor Immunity in Metastatic Cancer Patients [Human]

Project description:Fc-optimized CD40 Agonistic Antibody Induces Tertiary Lymphoid Structures and Systemic Antitumor Immunity in Metastatic Cancer Patients [Human]

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Agonistic anti-CD40 induces thyrocyte proliferation and promotes thyroid autoimmunity by increasing CD40 expression on thyroid epithelial cells.

Project description:CD40 is expressed on cells of the immune system and in some tissues that are targets for autoimmune-mediated damage. It is not known if CD40 expression in target tissues plays a role in the pathology of autoimmune diseases. This study shows that agonistic anti-CD40 induces strong and sustained proliferation of thyroid epithelial cells (TECs), or thyrocytes, in IFN-?(-/-) autoimmune-prone NOD and NOD.H-2h4 mice. TEC proliferation is accompanied by greatly increased expression of CD40 on TECs, development of fibrosis and hypothyroidism, and increased expression of proinflammatory molecules in thyroids. Bone marrow chimera experiments indicate that TEC expression of CD40 is required for anti-CD40-induced TEC proliferation, but lymphoid cells do not have to express CD40. TEC proliferation is reduced in wild-type mice given anti-CD40, presumably because they produce IFN-?, which inhibits TEC proliferation. CD40 also increases on TECs during development of an autoimmune thyroid disease characterized by TEC hyperproliferation that develops spontaneously in IFN-?(-/-) NOD.H-2h4 mice. TEC hyperproliferation development is accelerated in mice given agonistic anti-CD40. These studies provide new information regarding the role of target tissue expression of CD40 in development of autoimmunity and suggest that use of agonistic anti-CD40 for tumor therapy could result in autoimmune disease.

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Calorie Restriction Outperforms Bariatric Surgery in Reversing Obesity-Driven Tumor Progression in a Mouse Model of Triple Negative Breast Cancer-Study2_tumor

Project description:lean control, obese, and formerly obese C57BL6N mice which underwent weight loss via vertical sleeve gastrectomy or calorie restriction were injected with E0771 cells and tumor growth was monitored

2023-09-12 | GSE230471 | GEO

Calorie Restriction Outperforms Bariatric Surgery in Reversing Obesity-Driven Tumor Progression in a Mouse Model of Triple Negative Breast Cancer-RRBS

Project description:lean control, obese, and formerly obese C57BL6N mice which underwent weight loss via low-fat diet or verticle sleeve gastrectomy were injected with E0771 cells and tumor growth was monitored

2023-09-12 | GSE230473 | GEO

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