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Optimal pairing of binder and costimulatory domains improves dual CAR T cell efficacy

ABSTRACT: Optimal pairing of binder and costimulatory domains improves dual CAR T cell efficacy

PROVIDER: PRJNA1257323 | ENA |

REPOSITORIES: ENA

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Optimal pairing of binder and costimulatory domains improves dual CAR T cell efficacy

Project description:We explore whether introducing two chimeric antigen receptor (CAR) molecules with distinct signaling motifs into a single T cell improves CAR T cell (CART) efficacy against leukemia and lymphoma. RNA expression profiling demonstrated that T cells co-expressing two CARs that recognize the same target in which one CAR was linked to CD28 costimulation and the other was linked to 4-1BB costimulation augmented canonical NF-κB, non-canonical NF-κB, and Th17 differentiation pathways equivalently upon target engagement. Interestingly, multitargeted CARTs transcriptional profile favored the costimulatory domain linked to the binder of the more robustly expressed CD19 rather than one linked to the binder of the less expressed CD22 upon tumor engagement. In vivo and T cell exhaustion assays found that multitargeted T cells with distinct signaling domains led to greater durable control of B-ALL than single targeted Dual CAR T cells with T cells co-expressing CD19.BBζ and CD22.28ζ being the most potent. Together, this data indicates that optimal pairing of CAR binder domain with signaling cassette bolsters anti-tumor efficacy by improving both T cell durability and effector function.

2025-08-13 | GSE296016 | GEO

Costimulatory domains direct distinct fates of CAR-drivenT cell dysfunction

Project description:Costimulatory domains direct distinct fates of CAR-drivenT cell dysfunction

| PRJNA963196 | ENA

Application of Histone Interacting Domains as an Alternative to Antibodies (CIDOP-seq)

Project description:Application of Histone Modification Interacting Domains (HMIDs) as an Alternative to Antibodies. HMIDs and antibodies (taken from ENCODE) were used for precipitation of native chromatin (mononucleosomes) in order to study distinct histone marks. HMIDs used in this study are MPP8 Chromo domains and ATRX ADD (as H3K9me3 binders), Dnmt3a PWWP (as H3K36me3 binder) and CBX7 Chromo (as H3K27me3 binder).

2014-02-06 | E-MTAB-2143 | biostudies-arrayexpress

Costimulatory domains direct distinct fates of CAR-drivenT cell dysfunction [RNA-seq]

Project description:Costimulatory domains direct distinct fates of CAR-drivenT cell dysfunction [RNA-seq]

| PRJNA963195 | ENA

Costimulatory domains direct distinct fates of CAR-drivenT cell dysfunction [scRNA-seq]

Project description:Costimulatory domains direct distinct fates of CAR-drivenT cell dysfunction [scRNA-seq]

| PRJNA963197 | ENA

Costimulatory domains direct distinct fates of CAR-driven T cell dysfunction [ATAC-seq]

Project description:Costimulatory domains direct distinct fates of CAR-driven T cell dysfunction [ATAC-seq]

| PRJNA963194 | ENA

Differential susceptibility and role for senescence in CART cells based on costimulatory domains

Project description:Differential susceptibility and role for senescence in CART cells based on costimulatory domains

| PRJNA1226296 | ENA

Highly structured homolog pairing reflects functional organization of the Drosophila genome

Project description:Trans-homolog interactions encompass potent regulatory functions, which have been studied extensively in Drosophila, where homologs are paired in somatic cells and pairing-dependent gene regulation, or transvection, is well-documented. Nevertheless, the structure of pairing and whether its functional impact is genome-wide have eluded analysis. Accordingly, we generated a diploid cell line from divergent parents and applied haplotype-resolved Hi-C, discovering that homologs pair relatively precisely genome-wide in addition to establishing trans-homolog domains and compartments. We also elucidated the structure of pairing with unprecedented detail, documenting significant variation across the genome. In particular, we characterized two forms: tight pairing, consisting of contiguous small domains, and loose pairing, consisting of single larger domains. Strikingly, active genomic regions (A-type compartments, active chromatin, expressed genes) correlated with tight pairing, suggesting that pairing has a functional role genome-wide. Finally, using RNAi and haplotype-resolved Hi-C, we show that disruption of pairing-promoting factors results in global changes in pairing.

2018-10-16 | GSE121256 | GEO

Gene expression in self-activating CAR-T cells with CD28 or 4-1BB costimulatory domains.

Project description:We observed self-activation of SKM-CAR-T cells which target novel mesothelioma antigen. CAR-T with CD28 costimulatory domain showed signs of exhaustion while those with 4-1BB costimulatory domain did not. Changes in the gene expression by substituting CD28 co-stimulatory domain to 4-1BB co-stimulatory domain was investigated.

2023-05-28 | GSE231443 | GEO

MicroRNA 3'-compensatory pairing occurs through two binding modes, with affinity shaped by nucleotide identity and position [2]

Project description:MicroRNAs (miRNAs), in association with Argonaute (AGO) proteins, direct repression by pairing to sites within mRNAs. Compared to pairing preferences of the miRNA seed region (nucleotides 2–8), preferences of the miRNA 3′ region are poorly understood, due to the sparsity of measured affinities for the many pairing possibilities. We used RNA bind-n-seq with purified AGO2–miRNA complexes to measure relative affinities of >1,000 3′-pairing architectures for each miRNA. In some cases, optimal 3′ pairing increased affinity by >500-fold. Some miRNAs had two high-affinity 3′-pairing modes—one of which included additional nucleotides bridging seed and 3′ pairing to enable high-affinity pairing to miRNA nucleotide 11. The affinity of binding and the position of optimal pairing both tracked with the occurrence of G or oligo(G/C) nucleotides within the miRNA. These and other results advance understanding of miRNA targeting, providing insight into how optimal 3′ pairing is determined for each miRNA.

2022-03-31 | GSE196457 | GEO

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