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Tumor-activating IL2 rejuvenates intratumoral TIM3-CD8+T cell responses through targeting TIM3+CD8+T cell

ABSTRACT: Tumor-activating IL2 rejuvenates intratumoral TIM3-CD8+T cell responses through targeting TIM3+CD8+T cell

PROVIDER: PRJNA1261927 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR33537101_1.fastq.gz	Fastqsanger.gz
	SRR33537101_2.fastq.gz	Fastqsanger.gz
	SRR33537102_1.fastq.gz	Fastqsanger.gz
	SRR33537102_2.fastq.gz	Fastqsanger.gz
	SRR33537103_1.fastq.gz	Fastqsanger.gz

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Tumor-activating IL2 rejuvenates intratumoral TIM3-CD8+T cell responses through targeting TIM3+CD8+T cell

Project description:TIM3, a T-cell inhibitory receptor, is expressed on exhausted T cells in tumor microenvironment (TME). Anti-TIM3 antibody therapy could alleviate the suppression of tumor-infiltrating lymphocytes (TILs) in IL-2 dependent fashion. We hypothesize that high expression of TIM3 and limited IL-2 in TME facilitate immune evasion. To test that, we engineered anti-TIM3-pro-IL2 to selectively deliver IL-2 to TIM3high TILs by TIM3 antibody and reduce its toxicity with a cis delivery mechanism. Since IL-2 could reduce its activity at acidic pH inside TME, we also screened a low pH-selective IL-2 mutein (IL2V2) with enhanced affinity for IL-2Rβ. We then integrated pro-IL-2 into the anti-TIM3 antibodies in two different forms: TIM3-Rα-MMPs-IL2V2 (TIM3-ProIL2V2) as IL-2 release-form vs TIM3-IL2V2-MMPs-Rα as cis-form after binding to TIM3high T cells, ensuring the need of targeted delivery to TIM3-expressing TILs. Surprisingly, released IL2V2 from TIM3-Rα-MMPs-IL2V2 proved superior in anti-tumor immunity, but not cis delivery form TIM3-IL2V2-MMPs-Rα. Mechanistically, TIM3-ProIL2V2 not only reactivated TIM3+ TILs but also facilitated the activation and expansion of TIM3- T cells which in turn supported a sustained source of TIM3+ effector. TIM3-ProIL2V2 could control multiple tumor models including human tumor in humanized mice, confirming the hypothesis. TIM3-ProIL2V2 activates and expands TIM3-CD8+ T cells to overcome current major unmet medical need: anti-PD-1/L1 resistance. This strategy illustrates the potential of a tailored, low pH-resistant IL2 variant in invigorating both TIM3-negative and positive CD8+ T cells, offering a promising avenue for treating resistant tumors with reduced toxicity.

2025-05-22 | GSE296919 | GEO

Human CD8 T cell IL2 deprivation time course

Project description:IL2 deprivation time course for day 8 human CD8 T cells activated for 3 days with TransAct T-cell activation beads. PBMC (Cambridge Bio) were defrosted and CD8+ T-cells isolated using a human CD8+ T-cell isolation kit. CD8+ T-cells were activated at 1 x 106 cells/mL with 1 in 100 TransAct T-cell activation beads (Miltenyi) and 20 ng/mL IL-2 in complete RMPI (RMPI 1640, 10% FBS, penicillin/streptomycin) for three days. Cells were then washed out of activation and then maintained in complete RMPI with 20 ng/mL IL-2 for five days. To remove IL-2 for IL-2 deprivation, cells were washed twice in pre-warmed media, then replated in complete media without IL-2. Cells were deprived of IL-2 for 1hr, 3hrs, 5hrs, 8hrs, 24hrs or 48hrs.

2024-10-10 | PXD056475 | Pride

Molecular profiling of cultured CD8+ T cells from mice and treated with either IL2, IL2/SIIKFEKL(TCR), IL2/IL4, or IL2/IL4/SIINFEKL(TCR)

Project description:Molecular profiling of cultured CD8+ T cells from mice and treated with either IL2, IL2/SIIKFEKL(TCR), IL2/IL4, or IL2/IL4/SIINFEKL(TCR)

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Transcriptomic profiling of cultured CD8+ T cells from mice and treated with either IL2, IL2/SIINFEKL(TCR), IL2/IL4, or IL2/IL4/SIINFEKL(TCR)

Project description:Transcriptomic profiling of cultured CD8+ T cells from mice and treated with either IL2, IL2/SIINFEKL(TCR), IL2/IL4, or IL2/IL4/SIINFEKL(TCR)

| PRJNA432162 | ENA

ChIP-Seq of three H3 Acetylation epitopes in cultured CD8+ T cells from mice and treated with either IL2, IL2/SIINFEKL(TCR), IL2/IL4, or IL2/IL4/SIINFEKL(TCR)

Project description:ChIP-Seq of three H3 Acetylation epitopes in cultured CD8+ T cells from mice and treated with either IL2, IL2/SIINFEKL(TCR), IL2/IL4, or IL2/IL4/SIINFEKL(TCR)

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Identification of a T-bet hi Quiescent Exhausted CD8 T Cell Subpopulation That Can Differentiate into TIM3 + CX3CR1 + Effectors and Memory-like Cells

Project description:Persistent Ag induces a dysfunctional CD8 T cell state known as "exhaustion" characterized by PD-1 expression. Nevertheless, exhausted CD8 T cells retain functionality through continued differentiation of progenitor into effector cells. However, it remains ill-defined how CD8 T cell effector responses are sustained in situ. In this study, we show using the mouse chronic lymphocytic choriomeningitis virus infection model that CX3CR1+ CD8 T cells contain a T-bet-dependent TIM3-PD-1lo subpopulation that is distinct from the TIM3+CX3CR1+PD-1+ proliferative effector subset. The TIM3-CX3CR1+ cells are quiescent and express a low but significant level of the transcription factor TCF-1, demonstrating similarity to TCF-1hi progenitor CD8 T cells. Furthermore, following the resolution of lymphocytic choriomeningitis virus viremia, a substantial proportion of TCF-1+ memory-like CD8 T cells show evidence of CX3CR1 expression during the chronic phase of the infection. Our results suggest a subset of the CX3CR1+ exhausted population demonstrates progenitor-like features that support the generation of the CX3CR1+ effector pool from the TCF-1hi progenitors and contribute to the memory-like pool following the resolution of viremia.

2021-04-13 | GSE148497 | GEO

Pre-existing intratumoral stem-like CD8+ T-Cells drive radiotherapy-induced tumor control

Project description:To evaluate how intratumoral CD8+ T-cells are influenced by radiotherapy, we performed single-cell RNA sequencing of CD8+ T-cells sorted from MC38-OVA tumors 6 days after radiotherapy (single dose, 20Gy).

2025-03-24 | GSE279242 | GEO

Transcriptome differences in HCC infiltrated CD8+ T cells in effector and exhaustion state

Project description:CD8+ T cells isolated from HCC tissue were divided into three groups: PD1-TIM3- CD8+ TILs, exhibiting full effector function; PD1-intTIM3+ CD8+ TILs, exhibiting partial exhaustion; and PD1-hiTIM3+ CD8+ TILs, exhibiting severe exhaustion, as reflected by the differences in their ability to produce effector cytokines respectively. Transcriptome sequence analysis was performed to investigate the gene expression profile was performed.

2019-12-31 | E-MTAB-7278 | biostudies-arrayexpress

Transcriptional differences between intratumoral CD8+ T cells in young and aged tumors at single cell resolution

Project description:Single-cell RNA sequencing of intratumoral CD8+ T cells (and CD45+ cells) from young and aged mice

2024-03-14 | GSE255373 | GEO

SERT inhibits CD8 T cell antitumor immunity through regulating the intratumoral serotonin axis

Project description:Identifying new immune checkpoint molecules hindering antitumor T cell responses and devising new therapeutic blockades are key to the development of next-generation cancer immunotherapies. Here, we report the induction of the serotonin transporter (SERT) in solid tumor-infiltrating cytotoxic CD8 T cells, a molecule best known for its role in regulating serotonin neurotransmission in the brain. In solid tumors, CD8 T cells secrete serotonin, which stimulates their antitumor reactivities, while SERT functions as a negative regulator by depleting intratumoral serotonin. Inhibition of SERT using clinically approved selective serotonin reuptake inhibitors (SSRIs), a popular class of antidepressants, significantly suppressed tumor growth and enhanced CD8 T cell-mediated antitumor responses in various preclinical mouse syngeneic and human xenograft tumor models. Importantly, SSRI treatment exhibited significant therapeutic synergy with anti-PD-1 therapy, and clinical data correlation studies negatively associated intratumoral SERT expression with patient survival in a range of cancers. These findings highlight the significance of the intratumoral serotonin axis and identify SERT as a novel immune checkpoint, positioning SSRIs as promising candidates for next-generation combination cancer therapies.

2025-05-27 | GSE262781 | GEO

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