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Transient mTOR inhibition rescues 4-1BB-CAR-Tregs from tonic signal-induced dysfunction

ABSTRACT: Transient mTOR inhibition rescues 4-1BB-CAR-Tregs from tonic signal-induced dysfunction

PROVIDER: PRJNA761379 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15742877_1.fastq.gz	Fastqsanger.gz
	SRR15742877_2.fastq.gz	Fastqsanger.gz
	SRR15742878_1.fastq.gz	Fastqsanger.gz
	SRR15742878_2.fastq.gz	Fastqsanger.gz
	SRR15742879_1.fastq.gz	Fastqsanger.gz

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Transient mTOR inhibition rescues 4-1BB-CAR-Tregs from tonic signal-induced dysfunction

Project description:RNAseq analysis of human CAR-Tregs, bearing CD28 or 4-1BB as a costimulatory domains, initially isolated (before engineering) from peripheral blood of healthy donors

2021-09-07 | GSE183598 | GEO

Transient mTOR inhibition rescues 4-1BB CAR-Tregs from tonic signal-induced dysfunction.

Project description:The use of chimeric antigen receptor (CAR)-engineered regulatory T cells (Tregs) has emerged as a promising strategy to promote immune tolerance. However, in conventional T cells (Tconvs), CAR expression is often associated with tonic signaling, which can induce CAR-T cell dysfunction. The extent and effects of CAR tonic signaling vary greatly according to the expression intensity and intrinsic properties of the CAR. Here, we show that the 4-1BB CSD-associated tonic signal yields a more dramatic effect in CAR-Tregs than in CAR-Tconvs with respect to activation and proliferation. Compared to CD28 CAR-Tregs, 4-1BB CAR-Tregs exhibit decreased lineage stability and reduced in vivo suppressive capacities. Transient exposure of 4-1BB CAR-Tregs to a Treg stabilizing cocktail, including an mTOR inhibitor and vitamin C, during ex vivo expansion sharply improves their in vivo function and expansion after adoptive transfer. This study demonstrates that the negative effects of 4-1BB tonic signaling in Tregs can be mitigated by transient mTOR inhibition.

| S-EPMC8575891 | biostudies-literature

ATAC-seq profiling of human Tregs and conventional CD4+ cells that were transduced with a non-tonic signaling (CD19) or a tonic signaling (HA) CAR

Project description:Whether or not human Tregs are susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown. We studied how a tonic-signaling CAR, which induce Tconv exhaustion, affect human Tregs. We thus sorted naïve Tregs and naïve conventional CD4s and transduced them with a non-TS CAR (CD19) or a TS-CAR (HA).

2023-03-15 | GSE209835 | GEO

RNA-seq profiling of human Tregs and conventional CD4+ cells that were left untransduced or transduced with a non-tonic signaling (CD19) or a tonic signaling (HA) CAR

Project description:Whether or not human Tregs are susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown. We studied how a tonic-signaling CAR, which induce Tconv exhaustion, affect human Tregs. We thus sorted naïve Tregs and naïve conventional CD4s and either left them untransduced (UT) or transduced them with a non-TS CAR (CD19) or a TS-CAR (HA). After 12 days in culture, we isolated their RNA and did RNA sequencing.

2023-03-15 | GSE153384 | GEO

Tonic-signaling chimeric antigen receptors drive human regulatory T cell exhaustion

Project description:Whether or not human Tregs are susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown. We studied how a tonic-signaling CAR, which induces Tconv exhaustion, affects human Tregs. We thus sorted naïve Tregs and naïve conventional CD4s and transduced them with a non-TS CAR (CD19) or a TS-CAR (HA).

2022-07-28 | GSE209671 | GEO

Tregs constrain CD8+ T cell priming required for curative intratumorally anchored anti-4-1BB immunotherapy

Project description:Costimulation of T cells with agonist antibodies targeting 4-1BB (CD137) improves antitumor immune responses in preclinical studies, but clinical development has been hampered by on-target, off-tumor toxicity. Here, we report the development of a tumor-anchored ɑ4-1BB agonist, termed ɑ4-1BB-LAIR, which consists of an ɑ4-1BB antibody fused to the collagen binding protein mLAIR1. Combination treatment with an antitumor antibody (TA99) displayed only modest efficacy, but surprisingly cured >90% of mice upon depletion of CD4+ cells. We elucidated two mechanisms of action for this synergy: ɑCD4 increased priming and activation in the tumor draining lymph node , and TA99 + ɑ4-1BB-LAIR supported the cytotoxic program of these newly primed CD8+ T cells within the tumor microenvironment. Replacement of ɑCD4 with ɑCTLA-4, a more clinically relevant agent to enhance T cell priming, produces equivalently high cure rates while generating significantly more robust immunological memory against secondary tumor rechallenge.

2023-01-30 | GSE223087 | GEO

Tregs constrain CD8+ T cell priming required for curative intratumorally anchored anti-4-1BB immunotherapy

Project description:Tregs constrain CD8+ T cell priming required for curative intratumorally anchored anti-4-1BB immunotherapy

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The class-specific BCR tonic signal modulates lymphomagenesis in a transgenic model of c-myc transgene deregulation.

Project description:c-myc-3'RR mice developed Burkitt like lymphoma (IgM and IgD positive cells). We wished to study lymphomagenesis in mice carrying a modified B cell receptor with a higher level of tonic signal. The c-myc-3'RR transgene was introduced in a background with an IgH mutation that replaces IgM with IgA expression. Lymphoma arising in double mutant animals mostly carried the phenotype of activated cells, often expressing CD43, and in 10% of cases carrying a plasma cell phenotype. BCR tonic signal appears as a direct modulator of B cell malignancy phenotype. Burkitt lymphoma (BL) from 4 c-myc-3'RR mice, anaplastic (ANA) lymphoma from 4 c-myc-3'RR mice, CD43 negative lymphoma from 4 c-myc-IgA mice and CD43 positive lymphoma from 4 c-myc-IgA mice were investigated.

2012-02-01 | E-GEOD-32229 | biostudies-arrayexpress

Single-cell RNA sequencing reveals the transcriptomic characteristics of Tregs and TNFR2+ Tregs isolated from tumor tissues and peripheral blood of patients with gastric cancer

Project description:This study aimed to explore the characteristics and role of TNFR2+ Tregs in the microenvironment and progression of gastric cancer by single-cell RNA sequencing.We obtained Tregs from tumor tissues and peripheral blood of three GC patients.Through single-cell RNA sequencing, we found tumor-infiltrating Tregs express high levels of TNFR2. The TNF-a/TNFR2 signaling pathway is activated, accompanied by upregulation of costimulatory molecules. Compared to blood Tregs, tumor-infiltrating Tregs exhibit activated and effector states. In addition to expressing costimulatory molecules such as TNFR2, 4-1BB, OX40 and GITR, tumor-infiltrating Tregs are also characterized by high expression of immune checkpoints such as CTLA-4 and TIGIT and chemokines such as CCR6.This study revealed a high infiltration level of TNFR2+ Tregs with the characteristics of activated and effector Tregs in the tumor microenvironment. Our study provides a new theoretical basis for TNFR2+ Tregs as a therapeutic target in gastric cancer.

2021-04-16 | GSE172131 | GEO

ATAC-seq profiling of human Tregs and conventional CD4+ cells that were transduced with a non-tonic signaling (CD19) or a tonic signaling (HA) CAR

Project description:ATAC-seq profiling of human Tregs and conventional CD4+ cells that were transduced with a non-tonic signaling (CD19) or a tonic signaling (HA) CAR

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