Strength of CAR signaling determines T cell versus ILC differentiation from pluripotent stem cells
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ABSTRACT:
PROVIDER: PRJNA933190 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23385744.fastq.gz | Fastqsanger.gz | |||
| SRR23385745.fastq.gz | Fastqsanger.gz | |||
| SRR23385746.fastq.gz | Fastqsanger.gz | |||
| SRR23385747.fastq.gz | Fastqsanger.gz | |||
| SRR23385748.fastq.gz | Fastqsanger.gz |
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Project description:Generation of chimeric antigen receptor (CAR) T cells from pluripotent stem cells (PSCs) will enable advances in cancer immunotherapy. A detailed understanding of the effects of CARs on T cell differentiation from PSCs is important to this effort. The recently described artificial thymic organoid (ATO) system supports in vitro differentiation of PSCs to T cells. Unexpectedly, PSCs transduced with a CD19-targeted CAR resulted in diversion of T cell differentiation to the ILC2 lineage in ATOs. T cells and ILC2s are closely related lymphoid lineages which share certain developmental and transcriptional programs. Mechanistically, we show that antigen-independent CAR signaling during early lymphoid development was evident in ILC2-primed lymphoid precursors. We applied this understanding to rationally modulate CAR signaling strength through changes to CAR expression level, structure, or expression of cognate antigen and demonstrate that the T-versus-ILC lineage decision can be controlled in either direction, providing a framework for achieving normal CAR-T cell development from PSCs.
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Project description:Generation of chimeric antigen receptor (CAR) T cells from pluripotent stem cells (PSCs) will enable advances in cancer immunotherapy. Understanding how CARs affect T cell differentiation from PSCs is important for this effort. The recently described artificial thymic organoid (ATO) system supports in vitro differentiation of PSCs to T cells. Unexpectedly, PSCs transduced with a CD19-targeted CAR resulted in diversion of T cell differentiation to the innate lymphoid cell 2 (ILC2) lineage in ATOs. T cells and ILC2s are closely related lymphoid lineages with shared developmental and transcriptional programs. Mechanistically, we show that antigen-independent CAR signaling during lymphoid development enriched for ILC2-primed precursors at the expense of T cell precursors. We applied this understanding to modulate CAR signaling strength through expression level, structure, and presentation of cognate antigen to demonstrate that the T cell-versus-ILC lineage decision can be rationally controlled in either direction, providing a framework for achieving CAR-T cell development from PSCs.
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Project description:GFI1B determines specificity of lung tissue-resident multipotent ILC
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Project description:Purpose: Next-generation sequencing (NGS) has revolutionized the systems-based analysis of cellular pathways. The goals of this study are to compare NGS-derived transcriptome profiling (RNA-seq) between two generations of CAR-T cells aimed at integrating their fitness to overcome exhaustion and stress in tumor microenvironments Methods: mRNA profiles of CAR-T cells co-cultured with target cells for 48 hours were generated by deep sequencing. Human CD45 enrichment was performed to decrease tumor contamination. Results: Gene Set Enrichment Analysis (GSEA) of the RNA expression profile of T cells obtained 48 hours post co-culture with target cells demonstrated the enrichment of genes with memory T cell phenotype in B7H3 CAR-T compared to GD2-B7H3 T cells. However, B7H3 CAR-T cells were enriched in genes associated with glycolysis and apoptosis pathways suggesting a committed terminal fate for these T cells. There was significantly greater expression of genes attributed to exhaustion in B7H3 CAR-T cells than GD2-B7H3 T cells. In particular, B7H3 CAR-T cells showed higher expression of inhibitory receptors LAG3, HAVCR2 (TIM3), and BTLA genes, along with exhaustion-related transcription factor genes TBX21 (T-bet), PRDM1 (Blimp-1), and IKZF2 (Helios). B7H3 CAR-T cells also expressed genes that encode transcription factors reported to be associated with activated and memory T cells, such as KLF6, JUN, and JUNB. Conclusions: Our study represents the first analysis of transcriptome comparing SynNotch gated GD2-B7H3 CAR-T cells versus the conventional B7H3 CAR-T cells. GD2-B7H3 T cells exhibited superior resistance to exhaustion and greater metabolic fitness in comparison to conventional CAR-T cells. Metabolic preference (glycolytic versus oxidative) has an enormous impact on T cell fate. After eradicating NBL cells, GD2-B7H3 T cells had an oxygen consumption rate similar to UT cells, suggesting that the gated T cells can revert to their naïve metabolic state. Improved metabolic plasticity and reprogramming in favor of oxidative rather than glycolytic phosphorylation supports the hypothesis that the gated CAR-T cells likely have intact expansion potential, similar to unmanipulated naïve T cells. We observed significant enrichment of glycolytic genes in conventional B7H3 CAR-T cells compared to GD2-B7H3 T cells, supporting our metabolic studies. Our data suggest that SynNotch gated CAR-T cells have a more favorable oxidative metabolic profile than 4-1BB CAR-T cells.
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Project description:Innate lymphoid cells (ILCs) represent innate versions of T helper and cytotoxic T cells that differentiate from committed ILC precursors (ILCP). Still, how ILCP relate to mature tissue-resident ILCs remains unclear. We identify ILCP that are present in the blood and all tested lymphoid and non-lymphoid human tissues. Human ILCP fail to express the signature transcription factors (TF) and cytokine outputs of mature NK cells and ILCs but are epigenetically poised to do so. Human ILCP robustly generate all ILC subsets in vitro and in vivo. While human ILCP express RAR related orphan receptor C (RORC), circulating ILCP can be found in RORC-deficient patients that retain potential for EOMES+ NK cells, T-BET+ ILC1, GATA-3+ ILC2 and for IL-22+ but not for IL-17A+ ILC3. We propose a model of tissue ILC differentiation (‘ILC-poiesis’) whereby diverse ILC subsets are generated in situ from ILCP in response to environmental stressors, inflammation and infection.
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