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Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability

ABSTRACT: Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability

PROVIDER: PRJNA605702 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11050726.fastq.gz	Fastqsanger.gz
	SRR11050727.fastq.gz	Fastqsanger.gz
	SRR11050728.fastq.gz	Fastqsanger.gz
	SRR11050729.fastq.gz	Fastqsanger.gz
	SRR11050730.fastq.gz	Fastqsanger.gz

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Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability

Project description:Chimeric antigen receptor–T (CAR-T) cell therapies can eliminate relapsed and refractory tumors, but the durability of antitumor activity requires in vivo persistence. Differential signaling through the CAR costimulatory domain can alter the T cell metabolism, memory differentiation, and influence long-term persistence. CAR-T cells costimulated with 4-1BB or ICOS persist in xenograft models but those constructed with CD28 exhibit rapid clearance. Here, we show that a single amino acid residue in CD28 drove T cell exhaustion and hindered the persistence of CD28-based CAR-T cells and changing this asparagine to phenylalanine (CD28-YMFM) promoted durable antitumor control. In addition, CD28-YMFM CAR-T cells exhibited reduced T cell differentiation and exhaustion as well as increased skewing toward Th17 cells. Reciprocal modification of ICOS-containing CAR-T cells abolished in vivo persistence and antitumor activity. This finding suggests modifications to the costimulatory domains of CAR-T cells can enable longer persistence and thereby improve antitumor response.

2020-02-11 | GSE145007 | GEO

Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability.

Project description:Chimeric antigen receptor-T (CAR-T) cell therapies can eliminate relapsed and refractory tumors, but the durability of antitumor activity requires in vivo persistence. Differential signaling through the CAR costimulatory domain can alter the T cell metabolism, memory differentiation, and influence long-term persistence. CAR-T cells costimulated with 4-1BB or ICOS persist in xenograft models but those constructed with CD28 exhibit rapid clearance. Here, we show that a single amino acid residue in CD28 drove T cell exhaustion and hindered the persistence of CD28-based CAR-T cells and changing this asparagine to phenylalanine (CD28-YMFM) promoted durable antitumor control. In addition, CD28-YMFM CAR-T cells exhibited reduced T cell differentiation and exhaustion as well as increased skewing toward Th17 cells. Reciprocal modification of ICOS-containing CAR-T cells abolished in vivo persistence and antitumor activity. This finding suggests modifications to the costimulatory domains of CAR-T cells can enable longer persistence and thereby improve antitumor response.

| S-EPMC7260017 | biostudies-literature

Myeloid Niches Sustain Antitumor T Cells and License PD-1 Blockade via CD28 Costimulation

Project description:Myeloid Niches Sustain Antitumor T Cells and License PD-1 Blockade via CD28 Costimulation

| PRJNA738136 | ENA

The role of residue chirality of polypeptide hydrogels in regulating local immune microenvironment for anti-tumor immune responses

Project description:The impact of chirality on immune response has attracted great interest in cancer vaccine research recently. However, the study of chiral synthetic polypeptide hydrogels as cancer vaccines as well as of the impact of biomaterials itself for antitumor immunotherapy has rarely been reported. Herein, we demonstrated the key role of residue chirality of polypeptides hydrogels in antitumor immunity and local immune microenvironment regulation. Compared to poly(γ-ethyl-L-glutamate)-based hydrogels (L-Gel), poly(γ-ethyl-D-glutamate)-based hydrogels (D-Gel) induced greater immune cell infiltration. Unexpectedly, D-Gel caused higher levels of suppressive markers on antigen-presenting cells and even induced stronger T cells exhaustion than L-Gel. Finally, D-Gel established a local chronic inflamed and immunosuppressive microenvironment and showed insufficient anti-tumor effects. Conversely, the milder host immune responses induced by L-Gel led to more effective tumor inhibition. This study provides new insights on the role of residue chirality in the regulation of local immune microenvironment and affecting antitumor immune response.

2024-03-14 | GSE261299 | 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

Myeloid Niches Sustain Antitumor T Cells and License PD-1 Blockade via CD28 Costimulation

Project description:The local mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TILs) and responsiveness to PD-1 blockade remain partly elucidated. In human ovarian cancer we show that tumor-reactive intraepithelial (ie)CD8+ TILs engaged by antigen are polyfunctional and upregulate PD-1, which restrains their effectiveness. PD-1+ TILs exhibit a continuum of TCR-engaged/exhausted states with variable effector fitness related to CD28 costimulation, which they receive in intraepithelial niches involving myeloid antigen-presenting cells (mAPC). Following PD-1 blockade, activation of TILs requires CD28 costimulation mediated in situ by tumor mAPCs, which is locally enhanced by CTLA-4 blockade. CD40 ligand also amplifies TIL responses in situ, especially in tumors in which mAPCs are not activated. Thus, dysfunctional and exhausted TILs, in a state of TCR engagement but without proper CD28 costimulation by mAPCs in situ, are unlikely to fully benefit from PD-1 blockade.

2021-10-12 | GSE178245 | GEO

Profiling of Naïve (CD45RA+CD28+), EM (CD45RA-CD28-) and TEMRA (CD45RA+CD28-) CD8+ T cells

Project description:Profiling of Naïve (CD45RA+CD28+), EM (CD45RA-CD28-) and TEMRA (CD45RA+CD28-) CD8+ T cells

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Chimeric Antigen Receptors with a MyD88 and CD40 costimulatory endodomain endow T cells with superior antitumor activity

Project description:CAR T-cell therapy for solid tumors has shown limited efficacy in early phase clinical studies. The majority of CARs encode CD28 and/or 41BB costimulatory endodomains and we explored here if MyD88 and CD40 (MC) costimulatory endodomains in CARs improve their antitumor activity. We generated CD28-, 41BB-, and MC-CAR T-cells and demonstrate that MC-CAR T-cells have greater proliferative capacity and antitumor activity in repeat stimulation assays and in tumor models in vivo. Transcriptomic analysis revealed that MC-CAR T-cells expressed higher levels of MYB and FOXM1, key cell cycle regulators, and are activated at base line. After stimulation, MC-CAR T-cells remain in a less differentiated state than CD28- and 41BB-CAR T-cells as judged by low levels of TBET and BLIMP1 expression, and lower cytolytic activity in comparison to CD28- and 41BB-CAR T-cells. Thus, including MyD88 and CD40 signaling domains in CARs may improve current CAR T-cell therapy approaches for solid tumors.

2020-09-18 | GSE158144 | GEO

Gene expression in self-activating- and non-self-activationg CAR-T cells with CD28 or 4-1BB costimulatory domain.

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. To elucidate molecules responsible for self-activation-induced exhaustion, we performed RNA-seq analysis of SKM-CAR-T cells with CD28 or 4-1BB and CD19-CAR-T cells with CD28 or 4-1BB.

2022-08-19 | GSE211352 | GEO

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Project description:biogas residue compost Raw sequence reads

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