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Cooperative armoring of CAR and TCR T-cells by T cell-restricted IL-15 and IL-21 universally enhances solid tumor efficacy

ABSTRACT: Cooperative armoring of CAR and TCR T-cells by T cell-restricted IL-15 and IL-21 universally enhances solid tumor efficacy

PROVIDER: PRJNA955221 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24161412.fastq.gz	Fastqsanger.gz
	SRR24161413.fastq.gz	Fastqsanger.gz
	SRR24161414.fastq.gz	Fastqsanger.gz
	SRR24161415.fastq.gz	Fastqsanger.gz
	SRR24161416.fastq.gz	Fastqsanger.gz

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Cooperative armoring of CAR and TCR T-cells by T cell-restricted IL-15 and IL-21 universally enhances solid tumor efficacy

Project description:Chimeric antigen receptor (CAR) and T-cell receptor (TCR) T-cell therapies are effective in a subset of patients with solid tumors, but new approaches are needed to enhance efficacy and universally improve patient outcomes. IL-15 and IL-21 are common cytokine-receptor gamma chain family members with distinct, pleiotropic effects on T-cells and other lymphocytes. We found that self-delivery of these cytokines by CAR or TCR T-cells prevents functional exhaustion by repeated stimulation and limits the emergence of dysfunctional natural killer (NK)-like T-cells. Across different preclinical murine solid tumor models, we observe enhanced regression with each individual cytokine but the greatest anti-tumor efficacy when T-cells are armored with both. Thus, the co-expression of membrane-tethered IL-15 and IL-21 represents a technology to enhance the resilience and function of engineered T-cells against solid tumors and could be applicable to multiple therapy platforms and diseases.

2023-08-29 | GSE229651 | GEO

Cooperative Armoring of CAR and TCR T Cells by T Cell-Restricted IL15 and IL21 Universally Enhances Solid Tumor Efficacy.

Project description: Not available

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Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta

Project description:This SuperSeries is composed of the following subset Series: GSE36520: Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta [Affymetrix] GSE36554: Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta [Agilent] Refer to individual Series

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A developmentally restricted γδ T cell–IL-17A axis supports mouse heart regeneration [TCR-seq]

Project description:Mammalian heart regeneration is restricted to a brief postnatal period during which neonatal-specific mechanisms, including a tightly regulated immune response, enable tissue repair. Here, we show that cardiac injury during the regenerative window induces the accumulation of a distinct γδ T cell population that is absent from older non-regenerative hearts. Following injury, these cells serve as a rapid source of IL- 17A, which shapes the timing and composition of the neonatal immune response. Genetic ablation of γδ T cells or disruption of IL-17 signaling limits heart regeneration and results in dysregulated immune cell infiltration and impaired cardiac function. Mechanistically, our data suggest that γδ T cell-derived IL-17A acts on myeloid cells to initiate a rapid, self-limited inflammatory response that facilitates apoptotic cell clearance and limits sustained inflammation. Our study identifies a developmentally restricted immune axis that supports heart regeneration and advances our understanding of how neonatal-specific immune circuits shape tissue repair.

2026-09-08 | GSE344996 | GEO

A novel cooperative therapeutic regimen using gene fusion neoantigen-specific TCR-engineered T cells mediated sustained preclinical efficacy in solid tumors independent on inherent mutation profiling

Project description:Neoantigens derived from non-synonymous somatic mutations, especially gene fusion mutation, are restricted to tumor cells and thus considered ideal targets for T-cell receptor-engineering T-cells (TCR-T) immunotherapy. Adoptive transfer of neoantigen-specific TCR-T cells preferentially exhibit potent cytotoxicity preferentially to tumor cells, and has shown promising efficacy in several preclinical human cancer models. However, most neoantigens are unique to individual patient, which hinders the application of TCR-T cell therapy. In this study, we first discovered a paired / TCR repertoire, Tcr-1, that specifically targeted STY-SSX fusion neoantigen shared by almost all synovial sarcomas. Engineered T-cell expressing Tcr-1 (Tcr-T1) exhibited antigen-specific HLA-A*2402-restricted antitumoral activity against synovial sarcomas cell both in vitro and in vivo. Furthermore, to furtherly extend its application beyond synovial sarcomas, we innovatively developed a cooperative therapeutic modality, in which exogenous SYT-SSX fusion neoantigen was loaded into enzyme-responsive nanoparticles (NPs) formed by mPEG-PVGLIG-PCL copolymers (FNeo-AgNPs) for tumor targeting delivery. As expected, FNeo-AgNPs were proven of great tumor penetration, and local release. In situ modification was able to direct engineered Tcr-T1 against to other malignant gastric cancer cell line with significant antigen-specific HLA-A*2402-restricted cytotoxicity resulting in remarkable tumor regression and prolonging survival in both subcutaneous and peritoneally disseminated preclinical models, despite of their inherent mutation profiles. With these favorable data, our established cooperative therapeutic modality has a great potential for further clinical investigation, and provide a now insight for future TCR-T cell therapy development.

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A developmentally restricted γδ T cell–IL-17A axis supports mouse heart regeneration [TCR-seq]

Project description:A developmentally restricted γδ T cell–IL-17A axis supports mouse heart regeneration [TCR-seq]

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Macrophage-restricted Interleukin-10 receptor-, but not IL-10 deficiency causes severe spontaneous colitis

Project description:Interleukin-10 (IL-10) is a pleiotropic anti-inflammatory cytokine produced and sensed by most hematopoietic cells. Genome wide association studies and experimental animal models point at a central role of the IL-10 axis in Inflammatory Bowel Diseases. Here we investigated the importance of intestinal macrophage production of IL-10 and their IL-10 exposure, as well as the existence of an IL-10-based autocrine regulatory loop in the gut. Specifically, we generated mice harboring IL-10 or IL-10 receptor (IL-10R?) mutations in intestinal lamina propria-resident chemokine receptor CX3CR1hi-expressingmacrophages. We found macrophage-derived IL-10 dispensable for gut homeostasis and maintenance of colonic T regulatory cells. In contrast, loss of IL-10 receptor expression impaired the critical conditioning of these monocyte-derived macrophages, but resulted in spontaneous development of severe colitis. Collectively, our results highlight IL-10 as a critical homeostatic macrophage-conditioning factor in the colon and define intestinal CX3CR1hi macrophages as a decisive factor that determines gut health or inflammation. Microarray of resident macrophages sorted from colons of Interleukin-10 deficeint mice and macrophage-restricted interleukin-10 receptor deficient mice versus colonic resident macrophages of wild type mice

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A developmentally restricted γδ T cell–IL-17A axis supports mouse heart regeneration

2026-09-08 | GSE345008 | GEO

Specific targeting of the common gamma chain blocks cooperative reprogramming of human tissue-resident cytotoxic T lymphocytes by IL-15 and IL-21

Project description:The common gamma chain (γc) is required for productive signaling by interleukin (IL)-15, IL-21 and IL-2, which are critically involved in immune activation and regulation. IL-21 and IL-15 are implicated in the pathogenesis of type-1 diabetes, graft-versus-host disease, and celiac disease (CeD), a gluten-mediated autoimmune-like enteropathy. Attempts to treat type-1 diabetes and graft-versus-host disease with biologics targeting one particular cytokine have failed. Both IL-15 and IL-21 have been suggested to drive activation of cytotoxic T cells (CTL) that are the effectors mediating tissue destruction in CeD and organ-specific autoimmune disorders. We show that the concomitant upregulation of IL-15 and IL-21 occurs only in full-blown CeD with villous atrophy. BNZ-2, a peptide that targets the γc, was able to block the cooperative IL-15/IL-21 mediated transcriptional activation of human tissue-resident intraepithelial CTL. Importantly, this inhibition was specific and did not interfere with IL-2 signaling, a cytokine with known immunoregulatory functions. Moreover, BNZ-2 blocked gluten-induced IFN-γ production in small intestinal organ cultures from CeD patients. These observations identify BNZ-2 as a therapeutic candidate for immune disorders in which IL-15 and IL-21 cooperate to induce CTL-mediated tissue damage.

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A developmentally restricted γδ T cell–IL-17A axis supports mouse heart regeneration [RNA-seq]

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