Browse
Submit Data
Databases
API
Help

Dataset Information

12 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Improving the anti-solid tumor efficacy of CAR-T cells by inhibiting adenosine signaling pathway.

ABSTRACT: Chimeric antigen receptor T (CAR-T) cell therapy has been applied successfully in treating hematologic malignancies; however, it shows very limited efficacy in treating solid tumors. Adenosine is one of the key immunosuppressive metabolites in tumor microenvironment (TME) of solid tumors. Although the effect of adenosine has been well studied using mouse CAR-T cells, its effect on human CAR-T cells has not been fully elucidated. In particular, there was no evaluation of the CAR-T cells with blocked adenosine signaling in tumor xenograft animal model, which is essential for determining the feasibility of future clinical trials. In this study, we found the expression of A2a receptor (A2AR) and A2b receptor (A2BR) both upregulated in human-derived CAR-T cells, and only A2AR was responsible for adenosine-induced impairment of CAR-T cell function. Disrupting A2AR gene in human CAR-T cells with CRISPR-Cas9 increased the anti-tumor function and prevented the exhaustion of CAR-T cells in vitro. Furthermore, CRL5826-CDX model and two patient-derived xenograft solid tumor models were applied to evaluate the efficacy of A2AR knock-out CAR-T cells, which showed superior capability of inhibiting tumor growth. Taken together, these results demonstrate that A2AR knock-out CAR-T cells have the potential of being an improved CAR-T cell therapy in treating solid tumors.

SUBMITTER: Li N

PROVIDER: S-EPMC7781731 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Binding and Efficacy of Anti-Robo4 CAR-T Cells against Solid Tumors.

Project description:Chimeric antigen receptor expression T (CAR-T) cell therapy has been shown be efficacious against relapsed/refractory B-cell malignant lymphoma and has attracted attention as an innovative cancer treatment. However, cells of solid tumors are less accessible to CAR-T cells; moreover, CAR-T function is decreased in the immunosuppressive state of the tumor microenvironment. Since most tumors induce angiogenesis, we constructed CAR-T cells targeting roundabout homolog 4 (Robo4), which is expressed at high levels in tumor vascular endothelial cells, by incorporating three anti-Robo4 single-chain variable fragments (scFv) that were identified using phage display. We found that binding affinities of the three CARs to mouse and human Robo4 reflected their scFv affinities. More importantly, when each CAR-T cell was assayed in vitro, antigen-specific cytotoxicity, cytokine-producing ability, and proliferation were correlated with binding affinity for Robo4. In vivo, all three T-cells inhibited tumor growth in a B16BL6 murine model, which also correlated with Robo4 binding affinities. However, growth inhibition of mouse Robo4-expressing tumors was observed only in the model with CAR-T cells with the lowest Robo4 affinity. Therefore, at high Robo4 expression, CAR-T in vitro and in vivo were no longer correlated, suggesting that clinical tumors will require Robo4 expression assays.

| S-EPMC9220079 | biostudies-literature

Anti-CD19 CAR T cells potently redirected to kill solid tumor cells.

Project description:Successful CAR T cell therapy for the treatment of solid tumors requires exemplary CAR T cell expansion, persistence and fitness, and the ability to target tumor antigens safely. Here we address this constellation of critical attributes for successful cellular therapy by using integrated technologies that simplify development and derisk clinical translation. We have developed a CAR-CD19 T cell that secretes a CD19-anti-Her2 bridging protein. This cell therapy strategy exploits the ability of CD19-targeting CAR T cells to interact with CD19 on normal B cells to drive expansion, persistence and fitness. The secreted bridging protein potently binds to Her2-positive tumor cells, mediating CAR-CD19 T cell cytotoxicity in vitro and in vivo. Because of its short half-life, the secreted bridging protein will selectively accumulate at the site of highest antigen expression, ie. at the tumor. Bridging proteins that bind to multiple different tumor antigens have been created. Therefore, antigen-bridging CAR-CD19 T cells incorporate critical attributes for successful solid tumor cell therapy. This platform can be exploited to attack tumor antigens on any cancer.

| S-EPMC7971483 | biostudies-literature

Enhancing CAR-T cell efficacy in solid tumors by targeting the tumor microenvironment.

Project description:Chimeric antigen receptor (CAR)-T cell therapy has achieved successful outcomes against hematological malignancies and provided a new impetus for treating solid tumors. However, the efficacy of CAR-T cells for solid tumors remains unsatisfactory. The tumor microenvironment has an important role in interfering with and inhibiting the effector function of immune cells, among which upregulated inhibitory checkpoint receptors, soluble suppressive cytokines, altered chemokine expression profiles, aberrant vasculature, complicated stromal composition, hypoxia and abnormal tumor metabolism are major immunosuppressive mechanisms. In this review, we summarize the inhibitory factors that affect the function of CAR-T cells in tumor microenvironment and discuss approaches to improve CAR-T cell efficacy for solid tumor treatment by targeting those barriers.

| S-EPMC8093220 | biostudies-literature

Antrodia cinnamomea induces anti-tumor activity by inhibiting the STAT3 signaling pathway in lung cancer cells.

Project description:We examined the effects of an Antrodia cinnamomea ethanol extract (ACEE) on lung cancer cells in vitro and tumor growth in vivo. ACEE produced dose-dependent cytotoxic effects and induced apoptosis in Lewis lung carcinoma (LLC) cells. ACEE treatment increased expression of p53 and Bax, as well as cleavage of caspase-3 and PARP, while reducing expression of survivin and Bcl-2. ACEE also reduced the levels of JAK2 and phosphorylated STAT3 in LLC cells. In a murine allograft tumor model, oral administration of ACEE significantly inhibited LLC tumor growth and metastasis without affecting serum biological parameters or body weight. ACEE increased cleavage of caspase-3 in murine tumors, while decreasing STAT3 phosphorylation. In addition, ACEE reduced the growth of human tumor xenografts in nude mice. Our findings therefore indicate that ACEE inhibits lung tumor growth and metastasis by inducing apoptosis and by inhibiting the STAT3 signaling pathway in cancer cells.

| S-EPMC6435735 | biostudies-literature

Human sulfatase 1 exerts anti-tumor activity by inhibiting the AKT/ CDK4 signaling pathway in melanoma.

Project description:Human sulfatase 1 (hSulf-1) has aryl sulfatase activity. It can reduce the sulfation of cell surface heparan sulfate proteoglycan (HSPG) and inhibit various growth factor receptor-mediated signaling pathways. In most cancers, hSulf-1 is inactivated, which endows cancer cells with increasesed cell proliferation and metastatic activities, inhibition of apoptosis, and decreased sensitivity to radio- and chemotherapy. In this study, we found that hSulf-1 overexpression in melanoma cells can inhibit cell proliferation and induce cell cycle arrest and apoptosis by decreasing the protein kinase B (AKT) phosphorylation and limiting CDK4 nuclear import. We further confirmed that hSulf-1 overexpression can inhibit AKT phosphorylation and CDK4 nuclear localization and retard the growth of melanoma xenograft tumors in nude mice. Overall, hSulf-1 function in melanoma cells provides an ideal molecular treatment target. An important anti-tumor mechanism of hSulf-1 operates by decreasing downstream AKT signaling pathway activity and inhibiting the nuclear import of CDK4.

| S-EPMC5356675 | biostudies-literature

Anti-tumor efficacy of anti-GD2 CAR NK-92 cells in diffuse intrinsic pontine gliomas.

Project description:BackgroundDiffuse intrinsic pontine gliomas (DIPGs) are rare and fatal pediatric brainstem gliomas with no cure. Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have been proven effective in treating glioblastoma (GBM) in preclinical studies. However, there are no relevant studies on the CAR-NK treatment for DIPG. Our study is the first to evaluate the anti-tumor activity and safety of GD2-CAR NK-92 cells treatment for DIPG.MethodsFive patient-derived DIPG cells and primary pontine neural progenitor cell (PPC) were used to access disialoganglioside GD2 expression. Cell killing activity of GD2-CAR NK-92 cells was analyzed by in vitro cytotoxicity assays. Two DIPG patient-derived xenograft models were established to detect the anti-tumor efficacy of GD2-CAR NK-92 cells in vivo.ResultsAmong the five patient-derived DIPG cells, four had high GD2 expression, and one had low GD2 expression. In in vitro assays, GD2-CAR NK-92 cells could effectively kill DIPG cells with high GD2 expression while having limited activity against DIPG cells with low GD2 expression. In in vivo assays, GD2-CAR NK-92 cells could inhibit tumor growth in TT150630 DIPG patient-derived xenograft mice (high GD2 expression) and prolong the overall survival of the mice. However, GD2-CAR NK-92 showed limited anti-tumor activity for TT190326DIPG patient-derived xenograft mice (low GD2 expression).ConclusionOur study demonstrates the potential and safety of GD2-CAR NK-92 cells for adoptive immunotherapy of DIPG. The safety and anti-tumor effect of this therapy need to be further demonstrated in future clinical trials.

| S-EPMC10213244 | biostudies-literature

PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR-T cell efficacy in solid tumours

Project description:Although adoptive T cell therapy has shown remarkable clinical efficacy in hematological malignancies, its success in combating solid tumours has been limited. Here we report that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of adoptively transferred tumour-specific T cells. T cell-specific PTPN2 deficiency prevented tumours forming in aged mice heterozygous for the tumour suppressor p53. Adoptive transfer of PTPN2-deficient CD8+ T cells markedly repressed tumour formation in mice bearing mammary tumours. Moreover, PTPN2 deletion in T cells expressing a chimeric antigen receptor (CAR) specific for the oncoprotein HER-2 increased the activation of the Src family kinase LCK and cytokine-induced STAT-5 signalling, thereby enhancing both CAR-T cell activation and homing to CXCL9/10 expressing tumours to eradicate HER-2+ mammary tumours in vivo. Our findings define PTPN2 as a target for bolstering T-cell mediated anti-tumour immunity and CAR-T cell therapy against solid tumours.

| S-SCDT-EMBOJ-2019-103637 | biostudies-other

Trilobolide-6-O-isobutyrate exerts anti-tumor effects on cholangiocarcinoma cells through inhibiting JAK/STAT3 signaling pathway

Project description: Not available

| S-EPMC10915568 | biostudies-literature

Immunogenic chemotherapy enhances recruitment of CAR-T cells to solid tumors and improves anti-tumor efficacy when combined with checkpoint blockade

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-09-18 | GSE158111 | GEO

An IL-4/21 Inverted Cytokine Receptor Improving CAR-T Cell Potency in Immunosuppressive Solid-Tumor Microenvironment.

Project description:Incorporation of inverted cytokine receptor (ICR) such as interleukin (IL)-4 vs. IL-7 (4/7) ICR is one strategy to improve the antitumor activities of chimeric antigen receptor (CAR) modified T (CAR-T) cells facing immunosuppressive cytokines. Here we report a novel interleukin (IL)-4 vs. IL-21 ICR (4/21 ICR) that enhanced CAR-T cell potency in IL-4+ tumor milieu via a different working-mechanism from 4/7 ICR. Upon IL-4 stimulation, 4/21 ICR activated the STAT3 pathway and promoted Th17-like polarization and tumor-targeted cytotoxicity in CAR-T cells in vitro. Furthermore, 4/21 ICR-CAR T cells persisted and eradicated established IL-4+ tumors in vivo. Thus, 4/21 ICR is a promising clinical CAR-T cell therapeutics for solid tumors rich in IL-4.

| S-EPMC6658891 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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