Enhancing the anti-tumor efficacy of Bispecific T cell engagers via cell surface glycocalyx editing
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ABSTRACT:
PROVIDER: PRJNA1030938 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26463750_1.fastq.gz | Fastqsanger.gz | |||
| SRR26463750_2.fastq.gz | Fastqsanger.gz | |||
| SRR26463751_1.fastq.gz | Fastqsanger.gz | |||
| SRR26463751_2.fastq.gz | Fastqsanger.gz | |||
| SRR26463752_1.fastq.gz | Fastqsanger.gz |
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Project description:Bispecific T-cell engager (BiTE)-based cancer therapies that activate the cytotoxic T cells of a patient’s own immune system have gained momentum with the recent FDA approval of Blinatumomab for treating B cell malignancies. However, this approach has had limited success in targeting solid tumors. We have reported the development of BiTE-sialidase fusion proteins that enhance tumor cell susceptibility to BiTE-mediated cytolysis by T cells via targeted desialylation at the BiTE-induced T cell-tumor cell interface. Targeted desialylation results in better immunological synapse formation, T-cell activation and effector function. As a result, BiTE-sialidase fusion proteins show remarkably increased efficacy in inducing T-cell-dependent tumor cell cytolysis in response to target antigens compared to the parent BiTE molecules alone. This enhanced function is seen both in vitro and in in vivo xenograft and syngeneic solid tumor mouse models. Our findings highlight BiTE-sialidase fusion proteins as promising candidates for the development of next-generation bispecific T-cell engaging molecules for cancer immunotherapy. This transcriptomic dataset documents the effect of BiTE-sialidase vs uncojugated BiTE on T cells including the upregulation of effector associated genes.
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Project description:Adaptive immunotherapy including bispecific T cell engagers (TCE) has shown promise in the treatment of various cancers, but clinical responses are heterogeneous and often not durable. As response to TCE is suggested to be independent of tumor recognition and T cell state, molecular determinants or mediators of primary and acquired resistance towards TCE remain poorly understood. Here, we identify conserved behaviors of bone marrow residing CD4+ and CD8+ T cells in multiple myeloma patients undergoing TCE therapy. We show that the bone marrow immune landscape reacts to TCE therapy with cell state-dependent clonal T cell expansion and herewith infer coupling of tumor recognition via MHC-I, T cell exhaustion and clinical response. While we find the abundance of exhausted-like memory CD8+ T cell clones to be associated with clinical response failure, we describe loss of target epitope and MHC class I expression as tumor-intrinsic mechanisms of acquired resistance to TCE.
2022-10-28 | GSE216571 | GEO
Project description:Adaptive immunotherapy including bispecific T cell engagers (TCE) has shown promise in the treatment of various cancers, but clinical responses are heterogeneous and often not durable. As response to TCE is suggested to be independent of tumor recognition and T cell state, molecular determinants or mediators of primary and acquired resistance towards TCE remain poorly understood. Here, we identify conserved behaviors of bone marrow residing CD4+ and CD8+ T cells in multiple myeloma patients undergoing TCE therapy. We show that the bone marrow immune landscape reacts to TCE therapy with cell state-dependent clonal T cell expansion and herewith infer coupling of tumor recognition via MHC-I, T cell exhaustion and clinical response. While we find the abundance of exhausted-like memory CD8+ T cell clones to be associated with clinical response failure, we describe loss of target epitope and MHC class I expression as tumor-intrinsic mechanisms of acquired resistance to TCE.
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Project description:The glycocalyx consists of glycoproteins, glycolipids and extracellular polysaccharides at the cell surface which mediate viscoelastic and electrostatic barrier function. In molecular interactions the glycocalyx is thought to segregate locally to facilitate receptor-ligand binding, yet high-resolution maps of glycocalyx domains in cell-cell and cell-matrix interactions are lacking. We here applied TMTH-sulfoximine (THS)-based biorthogonal chemistry in live-cell culture and demonstrate much-enhanced glycocalyx detection, compared to established dibenzocyclooctyne-based labeling. Using superresolution microscopy, we identified micron-scale moderately diminished glycocalyx in cell-cell contacts and subtotal depletion in protrusions at the leading and trailing edges and membrane blebs when cells invaded 3D fibrillar matrix. At contacts to collagen fibrils, focal integrin clusters segregated in outward-protrusive nanodomains from glycocalyx (distance: 350 nm), forming adhesion sites of low glycocalyx content. Thus, THS-based next-generation bioorthogonal labelling of live cells identifies micro- and nanodomains with altered glycocalyx density, implicating local glycocalyx downregulation in functional cell-cell and cell-matrix interactions.
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Project description:Human cytomegalovirus is a ubiquitous herpesvirus that, while latent in most individuals, poses a great risk to immunocompromised patients. In contrast to directly acting traditional antiviral drugs, such as ganciclovir, we aim to emulate a physiological infection control using T cells. For this, we constructed several bispecific T-cell engager (BiTE) constructs targeting different viral glycoproteins of the murine cytomegalovirus and evaluated them in vitro for their efficacy. To isolate the target specific effect without viral immune evasion, we established stable reporter cell lines expressing the viral target glycoprotein B, and the glycoprotein complexes gN-gM and gH-gL, as well as nano-luciferase (nLuc). First, we evaluated binding capacities using flow cytometry and established killing assays, measuring nLuc-release upon cell lysis. All BiTE constructs proved to be functional mediators for T-cell recruitment and will allow a proof of concept for this treatment option. This might pave the way for strikingly safer immunosuppression in vulnerable patient groups.
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Project description:Adoptive cell therapy (ACT) utilizing γδ T cells is becoming a promising option for the treatment of cancer, because it offers an off-the-shelf allogeneic product that is safe, potent, and clinically effective. Approaches to engineer or enhance immune-competent cells for ACT, like expression of chimeric antigen receptors (CARs) or combination treatments with bispecific T cell engagers, have improved the specificity and cytotoxic potential of ACTs and have shown great promise in preclinical and clinical settings. Here, we test whether electroporation of γδ T cells with CAR or secreted bispecific T cell engager (sBite) mRNA is an effective approach to improve the cytotoxicity of γδ T cells. Using a CD19-specific CAR, approximately 60% of γδ T cells are modified after mRNA electroporation and these cells show potent anticancer activity in vitro and in vivo against two CD19-positive cancer cell lines. In addition, expression and secretion of a CD19 sBite enhances γδ T cell cytotoxicity, both in vitro and in vivo, and promotes killing of target cells by modified and unmodified γδ T cells. Taken together, we show that transient transfection of γδ T cells with CAR or sBite mRNA by electroporation can be an effective treatment platform as a cancer therapeutic.
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Project description:Bispecific antibodies are molecules with versatile modes of action and applications for therapy. They are commonly developed as T-cell engagers (TCE), which simultaneously target an antigen expressed by tumor cells and CD3 expressed by T-cells, thereby inducing T-cell-mediated target cell killing. There is growing evidence that the molecular composition and valency for the target antigen influence the activity of TCEs. Here, the eIg platform technology was used to generate a set of bispecific TCEs targeting epidermal growth factor receptors (EGFR) and CD3. These molecules either included or lacked an Fc region and exhibited one binding site for CD3 and either one or two binding sites for EGFR (1 + 1 or 2 + 1 formats) utilizing different molecular arrangements of the binding sites. In total, 11 different TCE formats were analyzed for binding to target cells and T cells, T cell-mediated killing of tumor cells, and for the activation of T cells (release of cytokines and proliferation of T-cells). Bivalent binding to EGFR strongly increased binding and T cell-mediated killing. However, the molecular composition and position of the CD3-binding arm also affected target cell killing, cytokine release, and T-cell proliferation. Our findings support that screening of a panel of formats is beneficial to identify the most potent bispecific TCE, and that format matters.
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