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

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

PROVIDER: PRJNA634347 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11826586_1.fastq.gz	Fastqsanger.gz
	SRR11826586_2.fastq.gz	Fastqsanger.gz
	SRR11826587_1.fastq.gz	Fastqsanger.gz
	SRR11826587_2.fastq.gz	Fastqsanger.gz
	SRR11826588_1.fastq.gz	Fastqsanger.gz

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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

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

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 domain-containing protein-10 (ADAM10)- and ADAM17-mediated cell surface shedding. Here, we show that mice expressing a metalloprotease-resistant, noncleavable LAG3 mutant (LAG3NC) are resistant to PD1 blockade and fail to mount an effective antitumor immune response. Expression of LAG3NC intrinsically perturbs CD4+ T conventional cells (Tconvs), limiting their capacity to provide CD8+ T cell help. Furthermore, the translational relevance for these observations is highlighted with an inverse correlation between high LAG3 and low ADAM10 expression on CD4+ Tconvs in the peripheral blood of patients with head and neck squamous cell carcinoma, which corresponded with poor prognosis. This correlation was also observed in a cohort of patients with skin cancers and was associated with increased disease progression after standard-of-care immunotherapy. These data suggest that subtle changes in LAG3 inhibitory receptor signaling can act as a resistance mechanism with a substantive effect on patient responsiveness to immunotherapy.

| S-EPMC7901539 | biostudies-literature

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

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

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

miRNA expression between CD4+PD1+ and CD4+PD1- T cells

Project description:Recent success in cancer immunotherapy has come from the blockade of inhibitory receptors on T cells, such as programmed cell death-1, which can induce a state of T cell exhaustion upon constant antigen stimulation. Understanding miRNA regulation of PD1 can be useful to discover miRNAs for use in therapy or as prognostic markers in various diseases including cancer, autoimmunity and transplantation. We used microarrays to discover global miRNA expression changes upon PD1 upregulation and identified miRNAs that are both up- and down-regulated. B16F10 cells were injected subcutaneously into C57BL/6 mice and 16 days later CD4+PD1+ and CD4+PD1- were sorted from the lymph nodes and spleen for RNA extraction and hybridization on Affymetrix miRNA array.

2015-08-01 | E-GEOD-65208 | biostudies-arrayexpress

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

Pathway Signatures Derived from On-treatment Tumor Specimens Predict Response to Anti-PD1 Blockade in Metastatic Melanoma

Project description:Both genomic and transcriptomic signatures have been developed to predict responses of metastatic melanoma to immune checkpoint blockade (ICB) therapies; however, most of these signatures were derived from pre-treatment biopsy samples. Here, we developed pathway-based signatures that predict response of metastatic melanoma to anti-PD1-based therapies in four independent datasets with RNAseq and clinical response data available for both pre- and on-treatment metastatic melanomas. We first identified pathway signatures that were significantly enriched in tumor specimens from anti-PD1 responders (R) compared to non-responders (NR) at pre-treatment and on-treatment time points, respectively. We also identified pathway signatures that were differentially expressed in pre-treatment versus on-treatment samples derived from R. Finally, we interrogated the capacity of the two types of signatures in predicting response of metastatic melanoma to anti-PD1 therapies in comparison with existing gene expression signatures. And we also investigated the effect of biopsy sites at the same biopsy time point on predictive performance of response to anti-PD1 therapy. Overall, we demonstrate that pathway-based signatures derived from on-treatment tumor specimens are highly predictive of response to anti-PD1 blockade therapies in patients with metastatic melanoma.

2021-08-15 | GSE168204 | GEO

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