Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Stimulation of oncogene-specific tumor infiltrating T-cells through combined vaccine and alpha-PD1 enable sustained anti-tumor responses against established HER2 breast cancer (BC) [RNA-Seq]

ABSTRACT: This study demonstrates two fundamental tenets of immunotherapy: vaccines targeting any tumor antigen will not be as effective as those targeting true oncogenic drivers and neither the stimulation of tumor-specific T-cells nor the blockade of a key immune checkpoint is enough to overcome the layers of immune suppression by itself. It provides single cell genetic evidence that vaccination alone generates a population of CD8 T-cells incapable of long-term tumor control due to the activation of numerous immune dysfunction pathways within the tumor. These promising studies have led to the initiation of a Phase II clinical trial testing a novel HER2 vaccine in combination with Pembrolizumab (NCT03632941) to determine if this combination can elicit effective anti-tumor immunity while minimizing off-target immune responses in patients with advanced HER2+ BC.

ORGANISM(S): Mus musculus

PROVIDER: GSE148477 | GEO | 2020/04/11

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Stimulation of oncogene-specific tumor infiltrating T-cells through combined vaccine and alpha-PD1 enable sustained anti-tumor responses against established HER2 breast cancer (BC) [WXS]

Project description:This study demonstrates two fundamental tenets of immunotherapy: vaccines targeting any tumor antigen will not be as effective as those targeting true oncogenic drivers and neither the stimulation of tumor-specific T-cells nor the blockade of a key immune checkpoint is enough to overcome the layers of immune suppression by itself. It provides single cell genetic evidence that vaccination alone generates a population of CD8 T-cells incapable of long-term tumor control due to the activation of numerous immune dysfunction pathways within the tumor. These promising studies have led to the initiation of a Phase II clinical trial testing a novel HER2 vaccine in combination with Pembrolizumab (NCT03632941) to determine if this combination can elicit effective anti-tumor immunity while minimizing off-target immune responses in patients with advanced HER2+ BC.

2020-04-11 | GSE148478 | GEO

Stimulation of oncogene-specific tumor infiltrating T-cells through combined vaccine and alpha-PD1 enable sustained anti-tumor responses against established HER2 breast cancer (BC) [scRNA-Seq]

2020-04-11 | GSE148480 | GEO

Bojungikki-Tang Enhances the Efficacy of Pembrolizumab Treatment in Human PBMC-Injected H460 Tumor-Bearing Mice

Project description:Immune checkpoint inhibitors (ICIs) have become a major treatment option for non-small cell lung cancer, but their efficacy is still limited because only a subset of patients responded to ICIs. Bojungikki-Tang (BJIKT), a widely used herbal medicine extracted from 10 medicinal plants, has been largely investigated as a combined treatment with anticancer agents. In this study, we examined the potential anti-tumor effect of co-administration of BJIKT and pembrolizumab in human peripheral blood mononuclear cell (PBMC)-injected H460 tumor-bearing MHC Ⅰ/Ⅱ double knockout NSG mice. We found that combination treatment with BJIKT and pembrolizumab significantly suppressed tumor growth by regulating the activation of immune cells. Immunohistochemistry analysis showed that the combination therapy decreased the exhausted proportion of CD8(+) and CD4(+) T cells expressing PD-1 and LAG-3 markers in the tumor tissues. Our transcriptome analysis indicated that BJIKT strengthened T cell function and TNF signaling and inhibited TGF-β signaling to induce cell cycle arrest and apoptosis. Additionally, BJIKT synergistically exhibited anti-tumor effects along with immune-related pathways when combined with pembrolizumab. Taken together, combination therapy altered immune cells and regulated anti-tumor immune response, paving the way for a more effective understanding of the role of BJIKT in the tumor microenvironment.

2024-03-05 | GSE260575 | GEO

Epigenetic priming enhances anti-tumor immunity in resistant ovarian cancer [RNA-Seq]

Project description:Here we describe the clinical and biological activity of guadecitabine, a second generation HMA, given in a low dose as a priming strategy before pembrolizumab, a humanized anti-PD1 antibody in a clinical trial for patients with recurrent, platinum resistant ovarian cancer. The methylomic and transcriptomic effects of the combination demonstrate readily activation of the anti-tumor immunity. High dimensional immune profiling of periferal mononuclear cells (PBMCs) and tumor biopsies obtained before and after treatment show distinct immune profiles and tissue architectural features associated with clinical benefit. Our study provides an in-depth view of the immune milieu of platinum resistant ovarian cancer and of the effects of the combination of HMAs and pembrolizumab on the interactions between immune cell populations and tumor cells.

2022-06-20 | GSE188249 | GEO

Epigenetic priming enhances anti-tumor immunity in resistant ovarian cancer [methylation array]

2022-06-20 | GSE186825 | GEO

Integrative multi-omics approach unveils underlying etiology of response to anti-PD1 in combination with anti-angiogenic therapy in recurrent ovarian cancer

Project description:Metastatic ovarian cancer lacks curative and therapeutic options in the recurrent setting, particularly refractory or platinum-resistant disease. Our phase 2 clinical trial (NCT02853318) combined pembrolizumab with bevacizumab to enhance T cell infiltration to the tumor microenvironment and oral cyclophosphamide to deplete regulatory T cells. This trial accrued 40 heavily pretreated recurrent ovarian cancer patients and resulted in an objective response rate of 47.5%, a median progression-free survival of 10 months, and disease control in 30% of patients over 12 months with good quality of life. To better assess the biological etiology underlying patient responses, we performed comprehensive molecular, immune, microbiome, and metabolic profiling in tumor, stroma, and fecal samples from patients on trial. Our unique findings point to predicted differences in T- and B-cell infiltration and glycerophospholipid dysregulation underlying combination therapeutic response. Overall, this study suggests the immune milieu may be leveraged as a target in non-responding patients to improve anti-tumor response and warrants further investigation.

2023-05-17 | GSE206422 | GEO

Expression data from syngeneic Hepa1-6 model in C57Bl/6J mice

Project description:Lenvatinib is an effective drug in advanced hepatocellular carcinoma (HCC). Its combination with the anti-PD1 immune checkpoint inhibitor pembrolizumab has achieved encouraging results in phase Ib and is currently being tested in phase III trials. Here, we aimed at exploring the molecular and immunomodulatory effects of lenvatinib alone or in combination with anti-PD1. We generated a syngeneic model of HCC in C57BL/6J mice and randomized the animals to receive placebo, lenvatinib, anti-PD1 or combination treatment. Transcriptomic analysis were performed to assess the expression profile of tumors from mice receiving each treatment strategy.

2023-04-07 | GSE153203 | GEO

HER2∆16 Engages ENPP1 To Promote an Immune Cold Microenvironment in Breast Cancer [tumor]

Project description:The tumor immune microenvironment (TIME) is a critical determinant of therapeutic response. However, the mechanisms regulating its modulation are not fully understood. HER2D16, an oncogenic splice variant of the human epidermal growth factor receptor (HER2), has been implicated in breast cancer and other tumor types as a driver of tumorigenesis and metastasis. Nevertheless, the underlying mechanisms of HER2Δ16-mediated oncogenicity remain poorly understood. Here, we show that HER2∆16 expression is not exclusive to the clinically HER2+ subtype and is associated with a poor clinical outcome in breast cancer. To understand how HER2 variants modulate the tumor microenvironment, we generated transgenic mouse models expressing either proto-oncogenic HER2 or HER2D16 in the mammary epithelium. We found that HER2∆16 tumors are immune cold, characterized by low immune infiltrate and an altered cytokine profile. Using an epithelial cell surface proteomic approach, we identified ENPP1 as a functional regulator of the immune cold microenvironment. We generated a knock-in model of HER2Δ16 under the endogenous promoter to understand the role of ENPP1 in aggressive HER2+ breast cancer. Knockdown of ENPP1 in HER2Δ16-derived tumor cells resulted in decreased tumor growth that was correlated with increased T-cell infiltration. These findings suggest that HER2Δ16-dependent ENPP1 activation is associated with aggressive HER2+ breast cancer through its immune modulatory function. Our study provides a better understanding of the mechanisms underlying HER2Δ16-mediated oncogenicity and highlights ENPP1 as a potential therapeutic target in aggressive HER2+ breast cancer.

2023-04-30 | GSE230179 | GEO

HER2 heterogeneity and treatment response-associated profiles in HER2-positive breast cancer in the NCT02326974 clinical trial

Project description:HER2-targeted therapies including antibody drug conjugates have shown great efficacy in HER2-positive breast cancer. However, resistance to treatment in part due to pre-existing HER2 heterogeneity (HET) is a significant clinical challenge and requires the use of rationally-designed combination therapies. Here we describe transcriptomic profiling of 287 biopsies from 129 patients in a phase II neoadjuvant clinical trial using a combination of T-DM1 and pertuzumab for early-stage HER2-positive breast cancer, we investigated the mechanisms driving T-DM1 resistance. In pre-treatment tumors from patients without a complete response (pCR), distinct molecular features were identified: HER2 HET tumors retained PI3K pathway activation and a basal-like phenotype, while HER2 Non-HET tumors exhibited lower PI3K pathway enrichment. T-DM1 treatment universally reduced HER2 protein expression and copy number heterogeneity while increasing PI3K pathway enrichment and luminal identity in residual tumors. Importantly, HER2 HET tumors showed minimal transcriptomic response compared to HER2 Non-HET tumors, in line with the lesser clinical response. The response to T-DM1 was not associated with hotspot PIK3CA/ERBB2 mutations but rather correlated with immune infiltration. HER2 Non-HET tumors exhibited less effective immune surveillance at baseline but became immune activated with T-DM1 treatment, while HER2 HET tumors exhibited a more immune suppressed microenvironment upon treatment. Our study highlights the multifaceted nature of T-DM1 resistance driven by HER2 heterogeneity and provides essential evidence for optimizing therapeutic strategies for these patients.

2024-02-29 | GSE243375 | GEO

The immunocytokine PD1-IL2v overcomes resistance to tumor immunity, and synergizes with anti-PD-L1

Project description:Immunotherapies have shown remarkable, albeit tumor-selective therapeutic benefits in the clinic. Here we evaluated the effects of the immunocytokine PD1-IL2v in a mouse model of de novo pancreatic neuroendocrine cancer resistant to checkpoint and other immunotherapies. PD1-IL2v is a bi-specific molecule based on a bivalent PD-1 antibody, serving as a targeting moiety, fused to an immuno-stimulatory IL-2 variant (IL2v) to precisely deliver IL2v to PD-1+ T-cells in the tumor microenvironment. PD1-IL2v elicited dramatic infiltration by CD8 T cells, notably stem-like and effector memory T cells, resulting in tumor regression and enhanced survival in mice. Furthermore, combining anti-PD-L1 with PD1-IL2v sustained the response phase, improving therapeutic efficacy both by reprogramming immunosuppressive tumor-associated macrophages and tumor endothelial cells , and by enhancing TCR immune repertoire diversity. The data motivate consideration of clinical trials to evaluate the combination therapy of PD1-IL2v and anti-PD-L1, especially in immunotherapy-resistant tumors infiltrated with PD-1+ T stem-like CD8 T cells.

2023-01-10 | GSE197854 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data