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Total RNA from cell lines (JurkatLAG+PD1+ and Raji-PDL1) treated with anti-PD1 antibody (MK3475) and/ or anti-LAG3 antibody (MK4280) was sequenced.

ABSTRACT: Total RNA from cell lines (JurkatLAG+PD1+ and Raji-PDL1) treated with anti-PD1 antibody (MK3475) and/ or anti-LAG3 antibody (MK4280) was sequenced.

PROVIDER: PRJNA833401 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18972458_1.fastq.gz	Fastqsanger.gz
	SRR18972458_2.fastq.gz	Fastqsanger.gz
	SRR18972459_1.fastq.gz	Fastqsanger.gz
	SRR18972459_2.fastq.gz	Fastqsanger.gz
	SRR18972460_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Total RNA from cell lines (JurkatLAG+PD1+ and Raji-PDL1) treated with anti-PD1 antibody (MK3475) and/ or anti-LAG3 antibody (MK4280) was sequenced.

Project description:A previously established bioassay using Jurkat cells overexpressing PD1 and Lag3 allowed for assessment of simultaneous blockade of PD1 and LAG3 pathways in an in-vitro setting and demonstrated that an antibody cocktail increased IL-2 levels 5-fold better than single agent treatment. To gain understanding of signal transduction events RNA-Seq analysis of cell pellets individually treated with LAG3 or PD1 antibodies was used to reveal modest immune activation however, 5-fold more genes were upregulated upon combination treatment. There were increases in costimulatory genes like CD28, CD5, CD6 as well as other intracellular signaling molecules like LCP2 and ITK. Given the role of ERK in immune activation of T cells, pERK levels of Jurkat cells in the assay were evaluated, indicating that ERK phosphorylation was impacted on PD1 and LAG3 engagement with their ligands and this could be reversed by antibody blockade. A small molecule phosphatase inhibitor NSC87877, when combined with the PD1 antibody, could phenocopy the effect of combining PD1 and LAG3 blocking antibodies. CD28 has a recognized role in PD1 signaling but the impact on LAG3 signaling remains unknown. CD28 knockout cells demonstrated an overall muted IL-2 response but retained combination benefit in terms of IL-2 production in the context of LAG3 and PD1 co-blockade versus individual antibody treatments. Taken together, these observations provide new insights on the impact of LAG3 and PD1 co-blockade and provides additional support for ongoing immunotherapy clinical trials that combine PD1 and LAG3 antibodies.

2023-07-29 | GSE201871 | GEO

Single-cell characterization of anti-LAG3+anti-PD1 treatment in melanoma patients

Project description:We evaluated blood samples from 6 patients with metastatic melanoma treated with anti-LAG3+anti-PD1 (160+480 mg) in a phase I trial (NCT01968109) using single-cell RNA and T cell receptor (TCR) sequencing (scRNA+TCRαβ-seq, 10X 5') combined with other multiomics profiling (flow, cytokine, TCRb-seq) from a larger cohort of 40 patients. This data set include three time points, including baseline, 1 month, and 3 month. The sorting is CD45+.

2023-02-03 | E-MTAB-12733 | biostudies-arrayexpress

LAG3 and PD1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN gamma-dependent anti-tumor immunity

Project description:Combined nivolumab (anti-PD1) and relatlimab (anti-LAG3) have shown enhanced effectiveness in melanoma patients. However, how these two receptors work together to hinder anti-tumor immunity remains unclear. Our study demonstrates that PD1/LAG3-deficient CD8+ T cells with more effectively clearing tumors and survive longer in melanoma mouse models. These PD1/LAG3-deficient CD8+ T cells have unique transcriptional profiles, broad TCR clonality, and enriched effector-like and interferon-responsive genes, leading to increased IFN gamma release indicating functionality. PD1 and LAG3 together drive T cell exhaustion, with a significant impact on TOX modulation. Mechanistically, autocrine IFN gamma signaling is crucial for enhancing anti-tumor immunity in PD1/LAG3-deficient CD8+ T cells, providing insights into the enhanced efficacy of combined PD1 and LAG3 targeting.

2024-08-07 | GSE262740 | GEO

Gene expression profile at single cell level of human TILs treated with PD1-TIM3, PD1-LAG3, anti-PD1 or control isotype.

Project description:Several next-generation cancer immunotherapies are designed to target LAG3 and TIM3 checkpoints, though the molecular and cellular mechanisms by which both receptors operate to mediate their anti-tumour effects are still poorly understood. Here, we examined the phenotypical and transcriptional consequences of treatment with bispecific antibodies (bsAbs), currently being tested in clinical trials, which co-target PD1 and either TIM3 or LAG3, respectively, using scRNAseq.

2022-07-16 | GSE208113 | GEO

Single-cell characterization of anti-LAG3+anti-PD1 treatment in melanoma patients

Project description:In this study, we analyzed the lymphocyte response to anti-LAG3+anti-PD1 treatment (relatilimab+nivolumab, phase I, NCT01968109) in prior and 4- and 12-week posttherapy blood samples from 40 metastatic melanoma patients using scRNA+TCRÃŽÂ±ÃŽÂ²-seq, flow cytometry, TCRÃŽÂ²-seq, and serum protein profiling together with ex vivo functional validations.

| EGAS00001005580 | EGA

Multiplex PRM quantitation of CD8a, CD4, LAG3, PD1, PD-L1 and PD-L2

Project description:Immuno-LC-PRM assay was developed to simultaneously quantify the expression levels of six immune markers (CD8A, CD4, LAG3, PD1, PD-L1 and PD-L2) using as little as 1-2 mg of fresh frozen tissue.

2018-10-04 | PXD011152 | Pride

Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding

Project description:Mechanisms of resistance to cancer immunotherapy remain poorly understood. Lymphocyte Activation Gene-3 (LAG3) signaling is regulated by A Disintegrin And Metalloprotease-10 (ADAM10) and ADAM17-mediated cell surface shedding. We developed and utilized mutant mice expressing a metalloprotease-resistance version of LAG3 that can be selectively expressed in T cell subsets. We sorted live T cells from tumors of mice bearing MC38 tumors following 3 treatments with either anti-PD1 or IgG control, and performed single-cell RNAseq using 10X 3' v2 reagents.

2020-05-22 | GSE150991 | GEO

Gene expression profile at single cell level of human TILs treated with PD1-TIM3, PD1-LAG3, anti-PD1 or control isotype.

Project description:Gene expression profile at single cell level of human TILs treated with PD1-TIM3, PD1-LAG3, anti-PD1 or control isotype.

| PRJNA858410 | ENA

Expression profile comparison of enriched bone marrow-derived tumor associated macrophages, tumor-associated alveolar macrophages, CD4 T cells, and total tumor-derived cells in lung cancer models with or without anti-PD1 and anti-VEGFA/ANGPT2 treatments.

Project description:Immune checkpoint blockade (ICB) with PD1 or PDL1 antibodies has been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of the patients respond and sustained remissions are rare. Both chemotherapy and anti-angiogenic drugs may improve tumor response to ICB in mouse models and patients with cancer. Here, we used genetically engineered mouse models of KrasG12D/p53null NSCLC, including a mismatch repair-deficient variant (KrasG12D/p53null/Msh2null) with higher mutational burden, and longitudinal imaging to study tumor response and resistance to combinations of ICB, anti-angiogenic therapy, and chemotherapy. Anti-angiogenic blockade of VEGFA and angiopoietin-2 markedly slowed progression of established tumors but, contrary to findings in other mouse cancer models, addition of a PD1 or PDL1 antibody was not beneficial and even accelerated progression of some of the tumors. We found that anti-angiogenic treatment facilitated tumor infiltration by PD1+ regulatory T cells (T-regs), which were more efficiently targeted by the PD1 antibody than CD8+ T cells. Both tumor-associated macrophages (TAMs) of bone-marrow origin, which are CSF1R-dependent, and TAMs of alveolar origin, which are sensitive to cisplatin, contributed to establishing a TGFB-rich tumor microenvironment that supported PD1+ T-regs. Dual TAM targeting with a combination of cisplatin and a CSF1R inhibitor fully abated T-regs, redirected the PD1 antibody to CD8+ T cells, and improved the efficacy of anti-angiogenic immunotherapy, achieving regression of the majority of the tumors.

2021-08-15 | GSE169194 | GEO

An Engineered IL-15 Cytokine Mutein Fused to an Anti-PD1 Antibody Improves Intratumoral T Cell Function and Anti-tumor Immunity (human)

Project description:Background: Cancer Immunotherapy with cytokines has demonstrated clinical efficacy but is frequently accompanied with severe adverse events caused by excessive and systemic immune activation. Here, we addressed these challenges by engineering a fusion protein of a single, potency-reduced, IL-15 mutein and an anti-PD1 antibody (αPD1-IL15m). This immunocytokine is designed to deliver PD1-mediated avidity-driven IL-2/15 receptor stimulation preferentially to PD1-positive tumor-infiltrating lymphocytes (TILs) while reducing the natural preference of IL-15 for circulating peripheral NK or T cell Methods: We isolated human lymphocytes from resected hepatocellular carcinoma tissue and cultured these tumor-infiltrating lymphocytes (TILs) in vitro in the presence or absence of an PD1-targeted IL15 mutein, anti-PD1 antibody or IL-15 agonist. After 9 days, CD4+ TILs and CD8+ TILs were sorted by FACS and RNA of 3,000 to 150,000 cells was isolated. Results: The PD1-IL15 fusion cytokine enhanced pro-survival, proliferation and activation pathways in tumor-infiltrating CD4+ and CD8+ cells compared to untreated controls as well as to the combined treatment of single agents (anti-PD1 antibody and IL-15 agonist)

2021-05-25 | GSE157893 | GEO

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