Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

NCI-H460 gene expression analysis after in vivo treatment with anti-PD1 antibody

ABSTRACT: Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 axis have made a breakthrough in the treatment of non-small cell lung cancer (NSCLC). However, a paradoxical boost in tumor growth was reported in a fraction of NSCLC patients after ICIs administration: a novel pattern of cancer progression defined “hyperprogressive disease” (HPD). Because the mechanism of HPD onset has not completely elucidated yet, this study aimed at investigating the cellular and molecular bases of this clinical phenomenon. Pre-treatment histological samples obtained from NSCLC patients were evaluated by immunohistochemistry (IHC) for immune cell infiltrate. Tissue samples from all patients with HPD showed tumor-infiltration by M2-like macrophages. To validate these findings in preclinical models, we utilized athymic nude mice that, lacking T-cells that may cloud the results, represent a suitable model to evaluate the role of macrophages in determining HPD. Immunodeficient mice were injected with human NSCLC NCI-H460 cell line, treated with anti-PD-1 antibody and tumor growth was evaluated over time. Anti-PD-1 treated H460 tumor-bearing mice showed HPD-like tumor growth as well as an increase in macrophage infiltration compared to control group. Interestingly, in these in vivo models, HPD-like growth, triggered by anti-PD-1 treatment, was dependent of anti-PD-1 antibody Fc domain. These results suggest that macrophages are the major players in HPD development and that FcR engagement on macrophages may determine a functional reprogramming of these immune cells toward a more aggressive and pro-tumorigenic phenotype, eventually inducing HPD.

ORGANISM(S): Mus musculus

PROVIDER: GSE210547 | GEO | 2023/01/11

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Effect of Non-small cell lung cancer (NSCLC) cell line conditioned medium (CM) on bone marrow-derived macrophages (BMDMs)

Project description:Hyperprogressive disease (HPD) is a newly described pattern of tumor progression characterizing a percentage of cancer patients receiving an immunotherapeutic regimen based on immune checkpoint inhibitors (ICIs), such as anti-PD1/PDL1 antibodies. Patients experiencing HPD are characterized by an unpredictable acceleration of tumor growth and a deterioration of the clinical conditions, rapidly leading to death. We have previously reported that macrophages play a pivotal role in contributing to HPD development. By analyzing non-small cell lung cancer (NSCLC) patient tumor samples, we observed that the tumor microenvironment (TME) of HPD-patients was infiltrated by particular clusters of macrophages. These macrophages are present before the initiation of ICI therapy and, therefore, we hypothesized that certain tumor cells may induce the acquisition of an “HPD-related” phenotype in macrophages that upon interaction with anti-PD1 antibody can unleash HPD. Since one of the strategies exploited by cancer cells to educate macrophage is to secrete molecules with immunomodulatory activity in the TME, bone marrow-derived macrophages (BMDMs) were exposed for 24 hours to the conditioned medium (CMs) obtained from five different NSCLC cell lines. We found that macrophages exposed to the CMs obtained from NCI-H460 and PC9 cell lines, reported to undergo a HPD-like growth in immunocompromised mice after anti-PD1 antibody treatment, have a gene expression profile completely different compared to the other experimental groups. Our findings suggest that soluble factors released by tumor cells can reprogram macrophages towards a phenotype potentially able to trigger HPD after interaction with anti-PD1 antibody.

2023-01-11 | GSE210340 | GEO

Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy [CD8 T]

Project description:Immune checkpoint inhibitors (ICIs) represented by anti-PD-1/PD-L1 antibodies have been widely applied for various cancers and the response rate to ICIs is closely associated with the tumor immune microenvironment (TIME). Here, we show that combinational targeting CCL7 and Fms-like tyrosine kinase 3 ligand (Flt3L) increases the infiltration and expansion of conventional type 1 dendritic cells (cDC1s) in tumor sites and enhances the T cell antitumor responses and the efficacy of anti-PD-1 therapy in subcutaneous tumor models and spontaneous KrasG12D non-small cell lung cancer (NSCLC) models. We demonstrate that the fusion protein PD-1Ab7 in which CCL7 is fused with the single chain fragment variable region of anti-PD-1 antibody (PD-1Ab) exhibits superior antitumor activities compared to PD-1Ab. Mechanistically, PD-1Ab7 promotes antitumor immunity by increasing the infiltration of cDC1s and the activation of T cells, which is severely compromised by depletion of Zbtb46+ cDCs or inhibition of the CCL7 receptor CCR2. Furthermore, complementation of Flt3L sensitizes the ICI-resistant tumors to PD-1Ab7 and synergizes with PD-1Ab7 to inhibit tumor progression. These findings highlight the essential roles of PD-1Ab-based chemokine fusion strategy in targeting cDC1s and T cells for cancer prevention and provide therapeutic lead molecules for antitumor immunotherapy.

2023-02-18 | GSE225163 | GEO

Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy [Dendritic Cell]

2023-02-18 | GSE225126 | GEO

ULK1 as a novel therapeutic target to enhance immune checkpoint therapies against melanoma

Project description:Immune checkpoint inhibitors (ICIs) have transformed the treatment of melanoma. However, the majority of patients have primary or acquired resistance to ICIs, limiting durable responses and patient survival. Interferon-gamma (IFNg) signaling and the expression of IFNg-stimulated genes correlate with either response or resistance to ICIs, in a context-dependent manner. While IFNg-inducible immunostimulatory genes are required for response to ICIs, chronic IFNg signaling induces the expression of immunosuppressive genes, promoting resistance to these therapies. Here, we show that high levels of ULK1 correlate with poor survival in melanoma patients and overexpression of ULK1 in melanoma cells enhances IFNg-induced expression of immunosuppressive genes, with minimal effects on the expression of immunostimulatory genes. In contrast, genetic or pharmacological inhibition of ULK1 reduces expression of IFNg-induced immunosuppressive genes. ULK1 binds IRF1 in the nuclear compartment of melanoma cells, controlling its binding to the PD-L1 promoter region. Additionally, pharmacological inhibition of ULK1 in combination with anti-PD-1 therapy further reduces melanoma tumor growth and enhances anti-tumor immune responses in vivo. Our data suggest that targeting ULK1 represses IFNg-dependent immunosuppression. These findings support the combination of ULK1 drug-targeted inhibition with ICIs for the treatment of melanoma patients to improve response rates and patient outcomes.

2023-02-02 | PXD035347 | Pride

Immune gene signatures for predicting durable clinical benefit of anti-PD-1 immunotherapy in patients with non-small cell lung cancer

Project description:Immune checkpoint blockade is promising for treating non-small-cell lung cancer (NSCLC). We used multipanel markers to predict the response to immune checkpoint inhibitors (ICIs) by characterizing gene expression signatures or individual genes in patients who showed durable clinical benefit to ICIs. Twenty-one patients with NSCLC treated with single-agent anti-programmed cell death protein (PD)-1 antibody were analyzed and their clinicopathological characteristics and response to ICIs were characterized. Targeted sequencing of tissue-extracted DNA and RNA was performed using the Oncomine Immune Response Research Assay to evaluate 395 genes involved in the immune response and calculate the tumor mutation burden. Nine (43%) showed a durable clinical benefit (DCB), while the remaining 12 (57%) patients showed non-durable benefit (NDB). The M1 and peripheral T cell signatures showed the best performance for discriminating DCB from NDB (sensitivity, specificity, accuracy = 0.89, 1.0, 0.95, respectively). Progression-free survival (PFS) was significantly longer in patients with high M1 signature or high peripheral T cell signature scores. CD137 and PSMB9 mRNA expression was higher in the DCB group than in the NDB group. Patients with high PSMB9 expression showed longer PFS. M1 signature, peripheral T cell signature and high mRNA expression level of CD137 and PSMB9 showed better predictive performance than known biomarkers (PD-L1, tumor infiltrating lymphocytes, tumor mutation burden). M1 and peripheral T cell signature of tumors may enable prediction of durable response and maximize the benefit of ICIs in patients with NSCLC.

2020-02-03 | GSE136961 | 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

Melanoma cell intrinsic GABAA receptor enhancement potentiates radiation and immune checkpoint inhibitor response by promoting direct and T cell-mediated anti-tumor activity

Project description:Most metastatic melanoma patients show variable responses to radiotherapy and do not benefit from immune checkpoint inhibitors (ICIs). Improved strategies for combination therapy that leverage potential benefits from radiotherapy and ICI are critical. Genes coding for subunits of GABAARs express functional GABAARs in melanoma cells. By enhancing GABAAR mediated anion transport, benzodiazepines depolarize melanoma cells and impair their viability. In vivo, benzodiazepine alone reduces tumor growth and potentiates radiotherapy and α-PD-L1 anti-tumor activity. Combination of benzodiazepine, radiotherapy, and α-PD-L1 results in near complete regression of treated tumors and a potent abscopal effect, mediated by increased infiltration of polyfunctional CD8+ T cells. Treated tumors show expression of cytokine:cytokine receptor interactions and overrepresentation of p53 signaling. This study identifies an anti-tumor strategy combining radiation and/or immune checkpoint inhibitor with modulation of GABAARs in melanoma using a benzodiazepine.

2020-10-23 | GSE159829 | GEO

Liu2023 - Predicting the efficacy of immune checkpoint inhibitors monotherapy in advanced non-small cell lung cancer: a machine learning method based on multidimensional data

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

MCL1 inhibition targets Myeloid Derived Suppressors Cells, promotes antitumor immunity and enhances the efficacy of immune checkpoint blockade

Project description:Immune checkpoint inhibitors (ICIs) are now the first line treatment for patients with advanced melanoma. Despite promising clinical results, many patients fail to respond to these therapies. BH3 mimetics, a novel class of small molecule inhibitors that bind and inhibit anti-apoptotic members of the BCL2 family proteins such as BCL2 or MCL1, have been very successful in treating hematologic malignancies. However, there are limited studies on the immunomodulatory role of the BH3 mimetics. Several factors contribute to ICI resistance including myeloid-derived suppressor cells (MDSCs) that exert immunosuppressive effects through direct and indirect inhibition of antitumor immunity. Thus, targeting MDSCs to enhance antitumor immunity has the potential to enhance the efficacy of ICIs. In this study, we show that the MCL1 inhibitor S64315 reduces melanoma tumor growth in an immune cell dependent manner in mice. Specifically, S64315 enhances antitumor immunity by reducing MDSC frequency and by promoting the activity of CD8+ T cells. Additionally, human MDSCs are 10 times more sensitive to S64315 than cutaneous melanoma lines. Further, we found that a higher expression of MCL1 is associated with poor survival for patients treated with anti-PD-1. Finally, combining S64315 and anti-PD-1 significantly slowed tumor growth compared to either agent alone. Together, this proof-of-concept study demonstrates the potential of combining MCL1 inhibitor with anti-PD-1 in the treatment of melanoma. It justifies the further development of next generation MCL1 inhibitors to improve efficacy of ICIs in treating malignant melanoma.

2024-03-01 | GSE249909 | GEO

ALPN-202 induces a more potent anti-tumor T cell response in MC38/hPD-L1 tumors than PD-L1 blockade alone

Project description:Purpose: Use RNA-seq to characterize the anti-tumor immune response induced by ALPN-202 and compare to that of anti-PD-L1 treatment alone. Methods: mRNA was isolated from MC38/hPD-L1 tumors 72 hours after a single dose of ALPN-202 (n=4), anti-PD-L1 mAb (durvalumab) (n=4), or Fc control (n=4). Results: ALPN-202 treatment resulted in elevated expression of multiple T cell, NK cell, myeloid cell genes. Additionally, there was a strong increase in genes commonly associated with a proinflammatory response including cytokines, chemokines and surface markers. Conclusions: ALPN-202 treatment resulted in a strong anti-tumor immune response that was more potent than that generated by blockade of PD-L1 alone.

2022-02-10 | GSE161244 | 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