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LFA-1 regulated by IL-2/STAT5 pathway boosts antitumor function of intratumoral CD8+ T cells for improving anti-PD-1 antibody therapy

ABSTRACT: LFA-1 regulated by IL-2/STAT5 pathway boosts antitumor function of intratumoral CD8+ T cells for improving anti-PD-1 antibody therapy

PROVIDER: PRJNA1047612 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27019136_1.fastq.gz	Fastqsanger.gz
	SRR27019136_2.fastq.gz	Fastqsanger.gz
	SRR27019137_1.fastq.gz	Fastqsanger.gz
	SRR27019137_2.fastq.gz	Fastqsanger.gz
	SRR27019138_1.fastq.gz	Fastqsanger.gz

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LFA-1 regulated by IL-2/STAT5 pathway boosts antitumor function of intratumoral CD8+ T cells for improving anti-PD-1 antibody therapy

Project description:These findings indicate that LFA-1-midiated immune synapse acts as a regulator of the antitumor function of intratumoral CD8+ T cells, which can be applied to improve anti-PD-1 antibody therapy.

2025-05-01 | GSE249184 | GEO

LFA-1 regulated by IL-2/STAT5 pathway boosts antitumor function of intratumoral CD8<sup>+</sup> T cells for improving anti-PD-1 antibody therapy.

Project description:Anti-PD-1 antibody therapy has achieved success in tumor treatment; however, the duration of its clinical benefits are typically short. The functional state of intratumoral CD8+ T cells substantially affects the efficacy of anti-PD-1 antibody therapy. Understanding how intratumoral CD8+ T cells change will contribute to the improvement in anti-PD-1 antibody therapy. In this study, we found that tumor growth was not arrested after the late administration of anti-PD-1 antibody and that the antitumor function of CD8+ T cells decreased with tumor progression. The results of the RNA sequencing of CD8+ T cells infiltrating the tumor site on days 7 and 14 showed that the cell adhesion molecule Lymphocyte Function-associated Antigen-1 (LFA-1) participates in regulating the antitumor function of CD8+ T cells and that decreased LFA-1 expression in intratumoral CD8+ T cells is associated with tumor progression. By analyzing the Gene Expression Omnibus (GEO) database and our results, we found that the antitumor function of intratumoral CD8+ T cells with high LFA-1 expression was stronger. The formation of immune synapses is impaired in Itgal-si CD8+ T cells, resulting in decreased anti-tumor function. LFA-1 expression in intratumoral CD8+ T cells is regulated by the IL-2/STAT5 pathway. The combination of IL-2 and anti-PD-1 antibody effectively enhanced LFA-1 expression and the antitumor function of intratumoral CD8+ T cells. The adoptive transfer of OT-1 T cells overexpressing LFA-1, STAT5A, or STAT5B resulted in higher antitumor function, deferred tumor growth, and prolonged survival. These findings indicate that LFA-1-mediated immune synapse acts as a regulator of the antitumor function of intratumoral CD8+ T cells, which can be applied to improve anti-PD-1 antibody therapy.

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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.

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Intratumoral NKT cell accumulation promotes antitumor immunity in pancreatic cancer

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Project description:Local immunotherapy ideally stimulates immune responses against tumors while avoiding toxicities associated with systemic administration. Current strategies for tumor-targeted, gene-based delivery, however, are limited by adverse effects such as off-targeting or anti-vector immunity. We investigated the intratumoral administration of saline-formulated messenger (m)RNA encoding four cytokines that were identified as mediators of tumor regression across different tumor models: interleukin (IL)-12 single chain, interferon (IFN)-α, granulocyte-macrophage colony-stimulating factor, and IL-15 sushi. Effective antitumor activity of these cytokines relied on multiple immune cell populations and was accompanied by intratumoral IFN-γ induction, systemic antigen-specific T cell expansion, increased granzyme B+ T cell infiltration, and formation of immune memory. Antitumor activity extended beyond the treated lesions and inhibited growth of distant tumors as well as disseminated tumors. Combining the mRNAs with immunomodulatory antibodies enhanced antitumor responses in both injected and uninjected tumors, thus improving survival and tumor regression. Consequently, clinical testing of this cytokine-encoding mRNA mixture is now underway.

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STAT5 is insufficient to drive steroid resistance in T-cell acute lymphoblastic leukemia despite activation of BCL2 and BCLXL upon glucocorticoid treatment

Project description:Overexpression of STAT5B_N642H mutant results in the ligand-independent activation of STAT5 signaling and STAT5 transcriptional activity, without affecting MAPK-ERK or PI3K-AKT signalling pathways. Overexpression of wild type (WT) STAT5B did not activate STAT5 signaling . Treatment with prednisolone boosts the expression of STAT5_N642H regulated genes, whereas NR3C1 can bind at gene loci of STAT5 regulated genes. Despite the steroid-enhanced upregulation of anti-apoptotic targets, the mutant cell line remaind sensitive to steroid treatment. We studied potential co-regulation and co-binding of NR3C1 and STAT5B in STAT5B_N642H and STAT5B_WT overexpressing cells, treated and untreated with prednisolone.

2022-10-01 | GSE171976 | GEO

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

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

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Intratumoral NKT cell accumulation promotes antitumor immunity in pancreatic cancer

Project description:Here, using the mouse KRT19-deficient (sgKRT19-edited) PDA model, we find that intratumoral accumulation of natural killer T (NKT) cells are required to establish an immunologically active TME. Mechanistically, intratumoral NKT cells facilitate type I interferon (IFN) production to initiate an anti-tumor adaptive immune response, and orchestrate the intratumoral infiltration of T cells, dendritic cells, natural killer cells and myeloid-derived suppressor cells. At the molecular level, NKT cells promote the production of type I IFN through the interaction of their CD40L with CD40 on myeloid cells. To evaluate the theraputical potential of these observations, we find that administration of folinic acid to mice bearing PDA increases NKT cells in the TME and improves their response to anti-PD-1 antibody treatment. In conclusion, NKT cells have an essential role in the immune response to mouse PDA and are potential targets for immunotherapy.

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