NB-resist
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB79225 | ENA |
REPOSITORIES: ENA
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Project description:In this comprehensive study, the authors have developed concise models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 Immune Checkpoint Blockade (ICB) treatment in individual tumors. It's important to note that their validation was performed in smaller, independent cohorts, constrained by data availability. The authors have developed two Logistic Regression based models for Ipilimumab treated and Ipilimumab naive patients with metastatic melanoma. The main predictive features for the Ipilimumab treated patients are MHC-II HLA, LDH at treatment initiation and the presence of lymph node metastases (LN met), chosen using forward selection methodology. The main predictive features for the Ipilimumab naive patients are tumor heterogeneity, tumor ploidy and tumor purity, chosen using forward selection methodology.
Please note that in these models, the output ‘1’ means progressive disease (PD) and ‘0’ means non-PD. The original GitHub repository can be accessed at https://github.com/vanallenlab/schadendorf-pd1
2023-11-17 | MODEL2310150001 | BioModels
Project description:Immune checkpoint blockade (ICB) has improved outcome for patients with metastatic melanoma but not all benefit from treatment. Several immune- and tumor intrinsic features are associated with clinical response at baseline. However, we need to further understand the molecular changes occurring during development of ICB resistance. Here, we collected biopsies from a cohort of 44 melanoma patients after progression to anti-CTLA4 or anti-PD1 monotherapy. Genetic alterations of antigen presentation and interferon gamma signaling pathways were observed in approximately 25% of ICB resistant cases. Anti-CTLA4 resistant lesions had a sustained immune response, including immune-regulatory features, as suggested by multiplex spatial and TCR clonality analyses. One anti-PD1 resistant lesion harbored a distinct immune cell niche, however, anti-PD1 resistant tumors were generally immune poor with non-expanded TCR clones. Such immune poor microenvironments were associated with melanoma cells having a de-differentiated phenotype lacking expression of MHC-I molecules. In addition, anti-PD1 resistant tumors had reduced fractions of PD1+ CD8+ T cells as compared to ICB naïve metastases. Collectively, these data show the complexity of ICB resistance and highlight differences between anti-CTLA4 and anti-PD1 resistance that may underlie differential clinical outcomes of therapy sequence and combination.
2024-02-06 | GSE244983 | GEO
Project description:Immune checkpoint blockade (ICB) has improved outcome for patients with metastatic melanoma but not all benefit from treatment. Several immune- and tumor intrinsic features are associated with clinical response at baseline. However, we need to further understand the molecular changes occurring during development of ICB resistance. Here, we collected biopsies from a cohort of 44 melanoma patients after progression to anti-CTLA4 or anti-PD1 monotherapy. Genetic alterations of antigen presentation and interferon gamma signaling pathways were observed in approximately 25% of ICB resistant cases. Anti-CTLA4 resistant lesions had a sustained immune response, including immune-regulatory features, as suggested by multiplex spatial and TCR clonality analyses. One anti-PD1 resistant lesion harbored a distinct immune cell niche, however, anti-PD1 resistant tumors were generally immune poor with non-expanded TCR clones. Such immune poor microenvironments were associated with melanoma cells having a de-differentiated phenotype lacking expression of MHC-I molecules. In addition, anti-PD1 resistant tumors had reduced fractions of PD1+ CD8+ T cells as compared to ICB naïve metastases. Collectively, these data show the complexity of ICB resistance and highlight differences between anti-CTLA4 and anti-PD1 resistance that may underlie differential clinical outcomes of therapy sequence and combination.
2024-02-06 | GSE244982 | GEO
Project description:Background: Outcomes for locally advanced or recurrent/ metastatic head and neck squamous cell carcinomas (HNSCCs) remain unfavorable despite recent advances with immune checkpoint blockade (ICB). Preclinical studies using model antigens identified a critical role of CD8+TCF7+PD1+ T cells in anti-PD1 response. Studies on the heterogeneity and clonal dynamics of global tumor infiltrating T lymphocytes (TILs) in the HNSCC anti-PD1 and anti-CTLA4 response have not been explored. Results: In this study, we generated isogenic HNSCC anti-PD1 sensitive/resistant models that bore distinct cancer cell intrinsic transcriptomic programs. Tumor microenvironment characterization using mass cytometry and targeted depletion revealed the contribution of Tregs and M2-like macrophages in anti-PD1 resistance. Paired single-cell RNA and TCR sequencing on tumor infiltrating immune cells from ICB responsive and resistant HNSCC models identified a spectrum of CD8+ TIL subsets including TCF7+PD1- (naïve/memory-like), TCF7+PD1+ (progenitor exhausted), and TCF7-PD1+ (terminally exhausted). Mapping TCR shared fractions between these subsets identified that successful anti-PD1 or anti-CTLA4 therapy induced higher post-treatment T cell lineage transitions. A TIL differentiation gene signature was associated with better responses in multiple ICB clinical trials. Conclusions: Together, analyses integrating scRNAseq and TCRseq demonstrate distinct differentiation dynamics of CD8+ TILs in novel ICB responsive and resistant HNSCC models, highlighting critical aspects of CD8+ TIL differentiation in response to ICB.
2021-12-01 | GSE153383 | GEO
Project description:Treatment with immunotherapy, particularly immune checkpoint blockade, can lead to benefit in the clinical setting. However, many preclinical and clinical studies suggest that resistance to anti-PD1 treatment frequently occurs, resulting in tumor relapse and treatment failure in cancer including hepatocellular carcinoma (HCC) patients. In this study ,10 HCC patients were treated with anti-PD1, and the biopsy samples before treatment were used for 289 nanostring panel RNA sequencing to compare responding and non-responding tumors to find possible pretreatment biomarkers or targets of the anti-PD1 therapy response
2022-06-20 | GSE198190 | GEO
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
Project description:Defining intrinsic and acquired mechanisms of immune checkpoint blockade resistance in glioblastoma
| PRJNA1102115 | ENA
Project description:PTEN deficiency is known to lead to tumor-intrinsic resistance to immune checkpoint blockade (ICB) treatment, especially in glioblastoma (GBM). We used RNA sequence to study the global gene expression and identified differentially expressed genes in PTEN knockdown GL261 cells, aiming to identify genes and pathways that are regulated by PTEN.
2021-03-06 | GSE157488 | GEO
Project description:Tumor-intrinsic signaling pathways can drastically affect the tumor immune microenvironment (TME), promoting tumor progression and resistance to immunotherapy by excluding immune cell populations from the tumor. Several tumor-cell intrinsic pathways have been reported to modulate myeloid cell infiltration and subsequent T cell recruitment. Clinical evidence suggests that excluding cytotoxic T cells from the tumor core mediates resistance to immunotherapy. Here, we find that tumor cell-intrinsic SOX2 expression in non-small cell lung cancer induces the exclusion of cytotoxic T cells from the tumor core and promotes resistance to checkpoint blockade therapy. CD8+ T cell exclusion was dependent on regulatory T cell-mediated suppression of tumor vasculature. Depleting tumor-infiltrating regulatory T cells via Glucocorticoid-Induced TNFR-Related protein (GITR) restored CD8+ T cell infiltration and, combined with checkpoint blockade therapy, reduced tumor growth.
2024-12-19 | GSE256071 | GEO
Project description:We report changes in B cells in patients treated with combination immune checkpoint blockade (CCB; anti-CTLA4 and anti-PD1)
2017-11-29 | GSE104600 | GEO