Molecular predictors of response to pembrolizumab in thymic carcinoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE181815 | GEO | 2021/08/31
REPOSITORIES: GEO
Similar Datasets
Project description:This study concurrently examined the genome, transcriptome, methylome and immune cell infiltrates in baseline tumors from advanced cutaneous melanoma patients treated with anti-PD-1 +/- anti-CTLA-4 immune checkpoint immunotherapy. Illumina MethylationEPIC BeadChip array analysis of 43 melanoma tumors was carried out as part of the study. Higher PSMB8 methylation (and therefore lower PSMB8 expression) was associated with poor response to immunotherapy. There were higher amounts of CD8+ T cells, as estimated by methylCIBERSORT, in the tumor microenvironment of good responders. Although we observed a significant correlation between PD-L1 expression and methylation of the cg197224470 CpG site, there was no significant difference between PD-L1 methylation in good and poor responders.
2021-12-09 | GSE181781 | GEO
Project description:Hepatocellular carcinoma (HCC) has dismal treatment responses to systemic therapies and is caused by both, viral and non-viral etiologies, including non-alcoholic steatohepatitis (NASH) 1–5. NASH - triggered by high caloric intake and sedentary lifestyle - has become an important driver for HCC development. Immunotherapy has been recently approved for HCC but stratification of responders versus non-responders has remained an unmet need 5–8. Here, we found a progressive accumulation of non-classical activated CD8+PD-1+ T-cells in livers of NASH-affected patients and mice. PD-L1/PD-1-targeted immunotherapy of NASH-induced HCC administered either at cancer-initiation or after cancer-establishment lacked beneficial effects in mice. On the contrary, PD-1-targeted immunotherapy drove hepatic necro-inflammation and increased liver cancer incidence, tumor number, and nodule size. Anti-CD8 or anti-CD8/anti-NK1.1 treatment suppressed liver cancer development, implicating CD8+ T-cells as liver cancer drivers in the context of NASH. In line, PD-1-/- mice challenged with a NASH-inducing diet displayed early-onset of liver cancer. Mechanistically, PD-1-targeted immunotherapy triggered necro-inflammation and a pro-tumorigenic environment in the context of NASH, increasing the abundance of hepatic TOX+CXCR6+ expressing CD8+PD-1+ TNF+ T-cells. Anti-CD8/anti-PD-1 or anti-TNF/anti-PD-1, but not anti-CD4/anti-PD-1 treatment reverted anti-PD1 treatment-related increase of liver inflammation, NASH severity and tumorigenesis. Gene expression profile and increased abundance of murine hepatic CD8+PD-1+ T-cells were corroborated in human CD8+PD-1+ T cells derived from NASH patients. In a meta-analysis of clinical trials testing PD-1-targeting immune checkpoint inhibitors alone (i.e. pembrolizumab) or in combination in 1656 patients with advanced HCC, immunotherapy was not favorable over to control treatment in non-viral- when compared to viral-related HCC. Similarly, in two clinical cohorts tested, patients with NASH-driven HCC had a significantly worse overall survival with PD-1-targeted immunotherapy than HCC patients with other etiologies. Our data identify non-viral etiologies, particularly NASH, as potentially non-responsive in the context of HCC immunotherapy, providing a strong rational basis for patient stratification.
2020-10-24 | GSE159977 | GEO
Project description:Immunotherapy has opened hitherto unknown possibilities to treat cancer. Whereas some cancer types (e.g. melanoma) can be efficiently treated, others lack measurable positive effects (e.g. PDAC). Moreover, stratification of responders/non-responders is only possible in some cancer types (e.g. melanoma). Hepatocellular carcinoma (HCC) has a dismal prognosis, limited treatment options and survival benefit, and represents a potential cancer entity for successful immunotherapy. Here, we investigated NASH-triggered HCC in the context PD-1-targeted immunotherapy. Using flow cytometry, single cell RNA sequencing, immunohistochemistry and mass spectrometric analyses, we found a progressive increase of CD8+PD-1+ effector T-cells with a unique profile of exhaustion and activation markers rising with murine and human NASH severity. Notably, late-stage HCC treatment with PD-1-targeted immunotherapy enhanced hepatic carcinogenesis in mice. Dissecting potential mechanisms of action during tumor-initiation and -progression we analyzed the effects of PD-1-targeted immunotherapy at HCC initiation. PD-1-targeted immunotherapy induced a pro-tumorigenic environment, enhanced necro-inflammation and increased NAFLD-activation score (NAS), leading to increased liver cancer incidence, tumor number and nodule size. In contrast, anti-CD8 or anti-CD8/anti-NK1.1 treatment reduced NAS and abrogated the development of liver cancer, thus identifying CD8+PD-1+ T-cells as drivers of liver cancer in NASH-triggered HCC. Increased apoptotic signaling, STAT3 phosphorylation and hepatic proliferation were detected in intra-tumoral liver tissue upon PD-1-targeted immunotherapy. In line, PD-1-/- mice challenged with a NASH diet displayed early onset of hepatocarcinogenesis, corroborating the pro-tumorigenic role of absent or reduced PD-1. Mechanistically PD-1-targeted immunotherapy mainly affected hepatic abundance of CD8+PD-1+ T-cells, instead of altering the quality of Tox+CXCR6+ expressing CD8+PD-1+TNF+CD39+Gzmb+ T-cells found in NASH livers, leading to an aggressive, pro-tumorigenic liver environment. Single-cell mapping of human NASH-, borderline NASH- or unaffected livers corroborated our preclinical NASH results. Moreover, in human NASH livers a correlation of hepatic CD8+, PD-1+, TNF+ T-cells with fibrosis and NASH severity was observed. Accordingly, HCC patients with NASH etiology display a sharp increase in intra- and peri-tumoral CD8+ PD-1+ T-cells. In a cohort of 65 patients recruited across 6 centers in Germany and Austria, patients with NAFLD/NASH-driven HCC responded worse to PD-1-targeted immunotherapy by Nivolumab or Pembrolizumab compared to non-NAFLD patients. This resulted in significant reduced overall survival, in trends of faster disease progression and reduced progression free survival. Histological analysis of livers derived from HCC patients treated with PD-1-targeted immunotherapy displayed high levels of intra and peri-tumoral CD8+ PD-1+ T-cells and Ki67+ hepatocytes. Taken together, these data indicate that PD-1-targeted immunotherapy induces immune-related adverse effects in NAFLD/NASH-driven HCC through CD8+PD-1+ T-cells. Our data call for stratification of HCC patients subjected to PD-1-targeted immunotherapy, with NAFLD being a negative predictor.
2021-03-03 | PXD017236 | Pride
Project description:Immunotherapy improves the survival of patients with advanced melanoma, 40% of whom become long-term responders. However, not all patients respond to immunotherapy. Further knowledge about the processes involved in response and resistance to immunotherapy is still needed. In this study, clinical paraffin samples from fifty-two advanced melanoma patients treated with anti-PD1 inhibitors were assessed by high-throughput proteomics and RNA-seq. The obtained proteomics and transcriptomics data were analyzed using network analyses based on probabilistic graphical models to identify those biological processes involved in response to immunotherapy. Additionally, proteins related to overall survival were studied.
2023-09-25 | PXD038155 | Pride
Project description:Immune checkpoint blockade has revolutionized cancer therapy. In particular, inhibition of programmed cell death protein 1 (PD-1) is effective for the treatment of metastatic melanoma and other cancers. Despite a dramatic increase in progression-free survival, a large proportion of patients do not show durable response. Therefore, predictive biomarkers of clinical response are urgently needed. Here, we employed high-dimensional single cell mass cytometry and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets in the peripheral blood of metastatic melanoma patients before and after anti-PD-1 immunotherapy. During therapy, we observed a clear treatment response to immunotherapy in the T cell compartment. However, prior to commending therapy a strong predictor of progression free and overall survival in response to anti-PD-1 immunotherapy was the frequency of CD14+CD16-HLA-DRhi monocytes. We could confirm this by conventional flow cytometry in an independent validation cohort and propose this as a novel predictive biomarker for therapy decisions in the clinic. In order to determine whether there are cell intrinsic changes in the monocyte signature, we performed RNA sequencing on sorted CD14+CD16-HLA-DRhi cells from HD, NR and R at baseline. Representative samples (n=4, each) of responders/non responders/ and healthy donors were selected from archival samples stored in the dermatology biobank according to the same clinical criteria used in the discovery and validation cohorts for CyTOF and FACS analysis. CD14+CD16-HLA-DRhiLin- (CD3, CD4, CD19, CD45RO) monocytes were sorted from frozen PBMC form blood samples from HD, R and NR at baseline.
2017-12-20 | E-MTAB-6214 | biostudies-arrayexpress
Project description:We profiled 70,781 peripheral immune cells taken before, during, and after treatment with chemotherapy and immunotherapy of patients with advanced gastrointestinal cancers using single cell RNA sequencing. Prior to therapy, responders had a higher relative abundance of undifferentiated (naïve) CD4+ T cells, while non-responders had more differentiated CD4+ and CD8+ effector memory (EM) cells. Further, the EM cells present in responders were exhausted, suggesting prior recognition of tumor. Upon anti-PD-1 treatment, T cells of responders showed a shift towards increased differentiation and a higher relative abundance of cytotoxic CD8+ T cells than non-responders, with both populations and monocytes showing striking activation of interferon and MHC processing pathways. In addition to T cells, responders were enriched in classical monocytes prior to therapy, with a predominance of high TNF-α and growth factor activity associated with inhibition of NF-κB. The number and signaling activation states of T cells and classical monocytes, as well as their evolution soon after the initiation of therapy, may be predictive markers of immunotherapy response.
2020-06-09 | GSE130157 | GEO
Project description:Immunotherapy has improved the prognosis of patients with advanced non-small cell lung
cancer (NSCLC), but only a small subset of patients achieved clinical benefit. The purpose of our study was to integrate multidimensional data using a machine learning method to predict the therapeutic efficacy of immune checkpoint inhibitors (ICIs) monotherapy in patients with advanced NSCLC.The authors retrospectively enrolled 112 patients with stage IIIB-IV NSCLC receiving ICIs monotherapy. The random forest (RF) algorithm was used to establish efficacy prediction models based on five different input datasets, including precontrast computed tomography (CT) radiomic data, postcontrast CT radiomic data, combination of the two CT radiomic data, clinical data, and a combination of radiomic and clinical data. The 5-fold cross-validation was used to train and test the random forest classifier. The performance of the models was assessed according to the area under the curve (AUC) in the receiver operating characteristic (ROC) curve. Among these models(RF MLP LR XGBoost), our reproduced onnx models have better performance, especially for random forest. The response variable with a value (1/0) indicates the (efficacy/inefficacy) of PD-1/PD-L1 monotherapy in patients with advanced NSCLC
2023-07-11 | BIOMD0000001074 | BioModels
Project description:Thymomas are one of the most rarely diagnosed malignancies. To better understand its biology and to identify therapeutic targets, we performed next-generation RNA sequencing. The RNA was sequenced from 13 thymic malignancies and 3 normal thymus glands. Validation of microRNA expression was performed on a separate set of 35 thymic malignancies. For cell-based studies, a thymoma cell line was used. Hierarchical clustering revealed 100% concordance between gene expression clusters and WHO subtype. A substantial differentiator was a large microRNA cluster on chr19q13.42 that was significantly overexpressed in all A and AB tumors and whose expression was virtually absent in the other thymomas and normal tissues. Overexpression of this microRNA cluster activates the PI3K/AKT/mTOR pathway. Treatment of a thymoma AB cell line with a panel of PI3K/AKT/mTOR inhibitors resulted in marked reduction of cell viability. A large microRNA cluster on chr19q13.42 is a transcriptional hallmark of type A and AB thymomas. Furthermore, this cluster activates the PI3K pathway, suggesting the possible exploration of PI3K inhibitors in patients with these subtypes of tumor. This work has led to the initiation of a phase II clinical trial of PI3K inhibition in relapsed or refractory thymomas. 13 thymic malignancies and 3 Normal Thymus RNA-Sequenced in triplicate
2016-04-06 | E-GEOD-79978 | biostudies-arrayexpress
Project description:Whereas some cancer types (e.g. melanoma) can be efficiently treated with immunotherapy, others lack measurable positive effects (e.g. PDAC ). Moreover, stratification of responders/non-responders is only possible in some cancer types (e.g. melanoma). Hepatocellular carcinoma (HCC) has a dismal prognosis, limited treatment options and survival benefit, and represents a potential cancer entity for successful immunotherapy. Here, we investigated NASH -triggered HCC in the context PD-1-targeted immunotherapy. Using flow cytometry, single cell RNA sequencing, immunohistochemistry and mass spectrometric analyses, we found a progressive increase of CD8+PD-1+ effector T-cells with a unique profile of exhaustion and activation markers rising with murine and human NASH severity. Notably, late-stage HCC treatment with PD-1-targeted immunotherapy enhanced hepatic carcinogenesis in mice. To dissect potential mechanisms of action during tumor-initiation and -progression we analyzed the effects of PD-1-targeted immunotherapy at HCC initiation. Anti-PD-1 treatment induced a pro-tumorigenic environment, enhanced necro-inflammation and increased NAFLD -activation score (NAS), leading to increased liver cancer incidence, tumor number and nodule size. In contrast, anti-CD8 treatment reduced NAS and abrogated the development of liver cancer, thus identifying CD8+PD-1+ T-cells as drivers of liver cancer in NASH-triggered HCC. Increased apoptotic signaling, STAT3 phosphorylation and hepatic proliferation were detected in intra-tumoral liver tissue upon PD-1-targeted immunotherapy. In line, PD-1-/- mice challenged with a NASH diet displayed early onset of hepatocarcinogenesis, corroborating the pro-tumorigenic role of absent or reduced PD-1. Mechanistically PD-1-targeted immunotherapy increased hepatic abundance of CD8+PD-1+Tox+CXCR6+CD8+PD-1+TNF+CD39+Gzmb+ T cells found in NASH livers, creating a pro-tumorigenic liver environment .
2021-01-19 | GSE144635 | GEO
Project description:Next generation sequencing of 28 thymic epithelial tumors (TETs) revealed a high frequency of GTF2I missense mutation (chr7:74146970T/A) in A thymomas, a relatively indolent subtype. The GTF2I mutation was confirmed in 82% of A and 74% of AB thymomas in a series of 274 TETs but was rare in aggressive subtypes, where recurrent mutations of known cancer genes were identified. Therefore, GTF2I mutation correlated with a better survival. GTF2I Beta and Delta isoforms were expressed in TETs and both mutant isoforms were able to stimulate cell proliferation in vitro. Thymic carcinomas presented a higher number of mutations than thymomas (average 43.5 and 18.4, respectively). Recurrent mutations of known cancer genes, including TP53, CYLD, CDKN2A, BAP1 and PBRM1 were identified in thymic carcinomas. These findings will complement the diagnostic work up of these rare tumors, and also help the development of a molecular classification, and assessment of prognosis and treatment strategies. Tumor samples of 286 patients were collected from 4 different institutions: National Cancer Institute (Bethesda MD), Pisa University Hospital (Pisa, Italy), Padua University Hospital (Padua, Italy) and IRCCS Istituto Clinico Humanitas (Rozzano, Italy).
2014-06-24 | E-GEOD-57892 | biostudies-arrayexpress