Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1130697 | ENA |
REPOSITORIES: ENA
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Project description:CAR-T cell therapy is effective in hematologic malignancies but not in solid tumors. In breast and lung cancer patients, CAR-T cells targeting ROR1 infiltrated tumors poorly and became dysfunctional. To test strategies for enhancing efficacy, we induced ROR1+ lung tumors in KrasLSL-G12D/+;p53fl/f mice. Murine ROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transiently controlled tumor growth but infiltrated tumors poorly and lost function, as observed in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen activated tumor macrophages to express T cell-recruiting chemokines, resulting in improved CAR-T cell infiltration, remodeling of the tumor microenvironment, and increased tumor sensitivity to anti-PD-L1. Combination therapy with Ox/Cy and anti-PD-L1 synergistically improved CAR-T mediated tumor control and survival, providing a strategy to improve CAR-T cell efficacy in the clinic.
2020-09-18 | GSE158109 | GEO
Project description:CAR-T cell therapy is effective in hematologic malignancies but not in solid tumors. In breast and lung cancer patients, CAR-T cells targeting ROR1 infiltrated tumors poorly and became dysfunctional. To test strategies for enhancing efficacy, we induced ROR1+ lung tumors in KrasLSL-G12D/+;p53fl/f mice. Murine ROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transiently controlled tumor growth but infiltrated tumors poorly and lost function, as observed in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen activated tumor macrophages to express T cell-recruiting chemokines, resulting in improved CAR-T cell infiltration, remodeling of the tumor microenvironment, and increased tumor sensitivity to anti-PD-L1. Combination therapy with Ox/Cy and anti-PD-L1 synergistically improved CAR-T mediated tumor control and survival, providing a strategy to improve CAR-T cell efficacy in the clinic.
2020-09-18 | GSE158110 | GEO
Project description:Targeting the PD-1/PD-L1 axis has transformed the field of immune-oncology. While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell‑intrinsic functions in immune and cancer cells. In line with these studies, here we show that PD-L1 potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cells resulted in enhanced infection with oncolytic viruses in cancer cells in vitro and in vivo. PD-L1 expression marks tumor explants from cancer patients that are best infected by oncolytic viruses. Agonistic antibodies targeting PD-L1 further reduced type I IFN responses and enhanced oncolytic virus infection. Mechanistically, PD-L1 suppressed type I interferon by promoting Warburg metabolism, characterized by enhanced glucose uptake and glycolysis rate. Lactate generated from glycolysis was the key metabolite responsible for inhibiting type I interferon responses and enhancing oncolytic virus infection in PD‑L1‑expressing cells. In addition to adding mechanistic insight into PD-L1 intrinsic function and showing that PD-L1 has a broader impact on immunity and cancer biology besides acting as a ligand for PD-1, our results will also help guide the numerous efforts currently ongoing to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.
2023-06-28 | GSE210884 | GEO
Project description:Biomaterial-based implants encapsulating islets or β-cells are desirable regimens for type 1 diabetes (T1D). However, current implants are restricted by poor durable β-cell survival due to immune cell infiltration, graft fibrosis and hypoxia. Programmed cell death-ligand 1 (PD-L1) induces T cell exhaustion, consequently protecting β-cells from autoimmune attack. Herein, we report an implant encapsulating PD-L1-overexpressing-β-cell microspheres (PD-L1 β-MCSs) and Chlorella within alginate hydrogel to control hyperglycemia in T1D. Virtually, PD-L1-β-cell derived exosomes efficaciously induce T cell exhaustion and convert macrophages into M2 phenotype in vitro. And PD-L1 β-MCSs secrete insulin in response to changes in glucose concentration. Furthermore, PD-L1-β-cell microspheres artificial Pancreas (PD-L1-β-MCSs aPancreas) prominently relieve hyperglycemia with less CD4+ T cells, CD8+ T cells, and M1 macrophages infiltration, inflammation and fibrosis deposition. Intriguingly, Chlorella produces oxygen to relieve hypoxia and enables the PD-L1-β-MCSs aPancreas-transplanted mice to achieve sustained normoglycemia, which potentially benefit from both oxygen supplementation and exosomal PD-L1.
2025-03-12 | PXD061778 |
Project description:The microtubule-stabilising drug paclitaxel has activity in relapsed ovarian cancer. However, resistance frequently develops. Oncolytic adenoviruses are a novel cancer therapy, and replicate selectively within and lyse malignant cells, leading to productive infection of neighbouring cells. We found increased efficacy of adenoviruses of multiple subtypes in paclitaxel-resistant ovarian cancer cells. There was increased expression of a key adenovirus receptor, CAR (coxsackie adenovirus receptor), due to increased transcription that resulted from histone modification. Moreover, CAR transcription increased in intraperitoneal xenografts with acquired paclitaxel resistance and in tumours from patients with paclitaxel-resistant ovarian cancer. Finally, we identified dysregulated cell cycle control as a second mechanism of increased adenovirus efficacy in paclitaxel-resistant ovarian cancer and that inhibition of CDK4/6 using PD-0332991 was able both to reverse paclitaxel resistance and reduce adenovirus efficacy. Thus, paclitaxel resistance increases oncolytic adenovirus efficacy via at least two separate mechanisms. Parental SKOV3 and paclitaxel-resistant SKOV3-TR cells were analysed in duplicate
2015-12-10 | E-GEOD-54772 | biostudies-arrayexpress
Project description:Disrupting PD-1/PD-L1 interaction rejuvenates antitumor immunity. Clinical successes by blocking PD-1/PD-L1 binding have grown across wide-ranging cancer histologies, but innate therapy resistance is evident in the majority of treated patients1. Cancer cells can express robust surface levels of PD-L1 to tolerize tumor-specific T cells, but regulation of PD-L1 protein levels in the cancer cell is poorly understood. Quasi-mesenchymal tumor cells up-regulate PD-L1/L2 and induce an immune-suppressive microenvironment, including expansion of M2-like macrophages and regulatory T cells and exclusion of CD8+ T-cell infiltration2. Targeted therapy, including MAPK inhibitor therapy in melanoma, leads to quasi-mesenchymal transitions and resistance3, and both MAPK inhibitor treatment and mesenchymal signatures are associated with innate anti-PD-1 resistance4,5. Here we identify ITCH as an E3 ligase that downregulates tumor cell-surface PD-L1/L2 in PD-L1/L2-high cancer cells, including MAPK inhibitor-resistant melanoma, and suppresses acquired MAPK inhibitor resistance in and only in immune-competent mice. ITCH interacts with and poly-ubiquitinates PD-L1/L2, and ITCH deficiency increases cell-surface PD-L1/L2 expression and reduces T cell activation. Mouse melanoma tumors grow faster with Itch knockdown only in syngeneic hosts but not in immune-deficient mice. MAPK inhibitor therapy induces tumor cell-surface PD-L1 expression in murine melanoma, recapitulating the responses of clinical melanoma3, and this induction is more robust with Itch knockdown. Notably, suppression of ITCH expression first elicits a shift toward an immune-suppressive microenvironment and then accelerates resistance development. These findings collectively identify ITCH as a critical negative regulator of PD-L1 tumor cell-surface expression and provide insights into previously unexplained role of PD-L1 in adaptive resistance to therapy.
2022-03-31 | MSV000089180 | MassIVE
Project description:We determined the immune cell composition and their gene expression, by performing single-cell RNA sequencing (scRNA-seq), in anti-PD-L1-treated 2F8cis tumors, a hot and immunoresponsive ovarian murine tumor model, and anti-PD-L1-treated 2F8cis/CA-MSC tumors. We also evaluated the ability of hedgehog inhibitor (HHi) therapy to reverse CA-MSC effects. Adipose-derived mesenchymal stem cells (MSC) were cultured with 2F8cis, an ovarian mouse tumor cell line, to generate cancer-associated MSC (CA-MSC). 2F8cis tumor cell alone or 2F8cis/CA-MSCs co-cultured cells at ratio 1:1 were injected into C57BL/6J mice. Tumor infiltrating CD45+ cells were isolated from anti-PD-L1-treated 2F8cis (Group 1, n=3), anti-PD-L1-treated 2F8cis/CA-MSCs (Group 2, n=3), anti-PD-L1+ IPI-926-treated 2F8cis/CA-MSCs (Group 3, n=3) tumors. Samples were labeled with different TotalSeq oligo-conjugated antibodies and loaded into the Chromium instrument (10x Genomics). The resulting barcoded cDNAs were used to construct libraries. Single-cell cDNA libraries were then processed for RNA sequencing using an Illumina NextSeq-500 platform. Anti-PD-L1-treated 2F8cis/CA-MSC tumors showed a high number of Monocytes and macrophages over-expressing Ccr2 and Tgfbi when compared to anti-PD-L1 responsive 2F8cis tumors. Our results also indicated that IPI-926 restored response to anti-PD-L1 therapy decresing the expression of Ccr2 and Tgfbi both in monocytes and macrophages. Our study represents the first detailed analysis generated by RNA-seq technology of 2F8cis/CA-MSC+ enriched tumor transcriptomes, treated with anti-PDL1 alone or in combination with HHi, and compared with anti-PDL1-treated tumors. The optimized data analysis workflows reported here should provide a framework for comparative investigations of expression profiles.
2021-10-06 | GSE185013 | GEO
Project description:This experiment aims to investigate how the overexpression of PD-L1 and SCE enhances the cytotoxic activity of CAR-NK cells against tumor cells. Pathway enrichment analysis revealed that CAR-NK cells with reduced HLA-ABC and overexpressed PD-L1 showed enrichment in proliferation and pro-inflammatory pathways. In contrast, CAR-NK cells with reduced HLA-ABC and overexpressed SCE exhibited enrichment in homeostasis-related pathways. On the other hand, cellular stress pathways were more prominently enriched in HLA-ABC reduced CAR NK cells following co-culture with target cells.
2025-08-20 | GSE276388 | GEO
Project description:PD-L1 suppresses host immunity and promotes tumor growth. We investigated how IFN-? regulates PD-L1 in the ovarian cancer microenvironment. In clinical samples, the number of stromal CTLs in peritoneally disseminated tumors was correlated with PD-L1 expression on the tumor cells, and the lymphocyte number was significantly related to the IFN-? signature score. In mouse models, PD-L1 was induced in peritoneal disseminated tumors, where lymphocytes were prominent, but not in subcutaneous tumors. Depleting IFNGR1 resulted in lower PD-L1 expression and longer survival in peritoneal dissemination model. Injection of IFN-? into subcutaneous tumors increased PD-L1 expression and tumor size, and PD-L1 depletion abrogated tumor growth. These data suggest that IFN-? works as a tumor progressor through PD-L1 induction. The source of IFN-? in ovarian cancer microenvironment and its biological effect to the tumor cells is unclear. The immortalized human ovarian surface epithelial cell line, HOSE-E7/hTERT (HOSE) was treated with IFN-? and expression microarray analysis was performed, and probes showing significantly higher values in IFN-?-added group were termed “IFN-? signature genes (295 probes)”. We then applied this signature to our ovarian cancer microarray data, which included 75 ovarian cancer clinical samples, by means of ss-GSEA. IFN-? signature score was strongly correlated to the number of infiltrating CD4-positive or CD8-positive lymphocytes in the tumors. These data suggest that the IFN-? in the ovarian cancer microenvironment is derived from lymphocytes, and an IFN-?-rich microenvironment is strongly correlated to a lymphocyte-rich microenvironment. Genome-wide transcriptional changes in human ovarian cancer tissue were observed in different tumor immunological microenvironment.
2014-03-04 | E-GEOD-55512 | biostudies-arrayexpress
Project description:Cancer cells develop mechanisms to escape immunosurveillance, among which modulating the expression of immune suppressive messenger RNAs is most well-documented. However, how this is molecularly achieved remains largely unresolved. Here, we develop an in vivo mouse model of liver cancer to study oncogene cooperation in immunosurveillance. We show that MYC overexpression (MYCTg) synergizes with KRASG12D to induce an aggressive liver tumor leading to metastasis formation and reduced mouse survival compared with KRASG12D alone. Genome-wide ribosomal footprinting of MYCTg;KRASG12 tumors compared with KRASG12D revealed potential alterations in translation of mRNAs, including programmed-death-ligand 1 (PD-L1). Further analysis revealed that PD-L1 translation is repressed in KRASG12D tumors by functional, non-canonical upstream open reading frames in its 5′ untranslated region, which is bypassed in MYCTg;KRASG12D tumors to evade immune attack. We show that this mechanism of PD-L1 translational upregulation was effectively targeted by a potent, clinical compound that inhibits eIF4E phosphorylation, eFT508, which reverses the aggressive and metastatic characteristics of MYCTg;KRASG12D tumors. Together, these studies reveal how immune-checkpoint proteins are manipulated by distinct oncogenes at the level of mRNA translation, which can be exploited for new immunotherapies.
2019-01-07 | GSE105147 | GEO