Osteopontin links acquired resistance to hypoxia-inducing antiangiogenics with refractoriness to anti-PD-L1 agents in breast cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE241539 | GEO | 2026/05/05
REPOSITORIES: GEO
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| GSE241539_RAW.tar | Raw | |||
| filelist.txt | Txt |
Items per page: 5 1 - 3 of 3 |
Similar Datasets
Project description:Resistance to antiangiogenics is a major challenge in cancer therapy. These agents can either normalize or exacerbate tumor vascular abnormality and hypoxia. The mechanisms of resistance remain unclear in the latter setting. By integrating data from mouse models and clinical trials, we show that hypoxia-inducing anti-VEGF therapy upregulates programmed cell death ligand 1 (PD-L1), yet fails to sensitize tumors to PD-L1 blockade. Mechanistically, early hypoxic stress triggers epithelial osteopontin (Spp1) production, which recruits monocytes and skews macrophages toward M2 states, suppressing T-cell cytotoxicity. Pharmacologic Spp1 depletion impedes the development of hypoxia, M2 infiltration, restores T-cell activity and enables synergy between antiangiogenics and anti-PD-L1. Genetic dissection – tumor-epithelial Spp1 knockout grafts and bone-marrow chimeras generated by lethal irradiation and reconstitution with Spp1-/- or wild-type hematopoietic donors – show that myeloid Spp1 contributes only marginally compared with epithelial Spp1. These findings identify Spp1 as a central mediator of resistance to hypoxia-inducing antiangiogenics, contribute to a comprehensive model of antiangiogenic resistance, and support Spp1-targeted strategies to personalize immuno/antiangiogenic therapy according to tumor hypoxia.
2026-04-28 | GSE328950 | GEO
Project description:Resistance to antiangiogenics is a major challenge in cancer therapy. These agents can either normalize or exacerbate tumor vascular abnormality and hypoxia. The mechanisms of resistance remain unclear in the latter setting. By integrating data from mouse models and clinical trials, we show that hypoxia-inducing anti-VEGF therapy upregulates programmed cell death ligand 1 (PD-L1), yet fails to sensitize tumors to PD-L1 blockade. Mechanistically, early hypoxic stress triggers epithelial osteopontin (Spp1) production, which recruits monocytes and skews macrophages toward M2 states, suppressing T-cell cytotoxicity. Pharmacologic Spp1 depletion impedes the development of hypoxia, M2 infiltration, restores T-cell activity and enables synergy between antiangiogenics and anti-PD-L1. Genetic dissection – tumor-epithelial Spp1 knockout grafts and bone-marrow chimeras generated by lethal irradiation and reconstitution with Spp1-/- or wild-type hematopoietic donors – show that myeloid Spp1 contributes only marginally compared with epithelial Spp1. These findings identify Spp1 as a central mediator of resistance to hypoxia-inducing antiangiogenics, contribute to a comprehensive model of antiangiogenic resistance, and support Spp1-targeted strategies to personalize immuno/antiangiogenic therapy according to tumor hypoxia.
2026-04-22 | GSE328461 | GEO
Project description:Resistance to antiangiogenics is a major challenge in cancer therapy. These agents can either normalize or exacerbate tumor vascular abnormality and hypoxia. The mechanisms of resistance remain unclear in the latter setting. By integrating data from mouse models and clinical trials, we show that hypoxia-inducing anti-VEGF therapy upregulates programmed cell death ligand 1 (PD-L1), yet fails to sensitize tumors to PD-L1 blockade. Mechanistically, early hypoxic stress triggers epithelial osteopontin (Spp1) production, which recruits monocytes and skews macrophages toward M2 states, suppressing T-cell cytotoxicity. Pharmacologic Spp1 depletion impedes the development of hypoxia, M2 infiltration, restores T-cell activity and enables synergy between antiangiogenics and anti-PD-L1. Genetic dissection – tumor-epithelial Spp1 knockout grafts and bone-marrow chimeras generated by lethal irradiation and reconstitution with Spp1-/- or wild-type hematopoietic donors – show that myeloid Spp1 contributes only marginally compared with epithelial Spp1. These findings identify Spp1 as a central mediator of resistance to hypoxia-inducing antiangiogenics, contribute to a comprehensive model of antiangiogenic resistance, and support Spp1-targeted strategies to personalize immuno/antiangiogenic therapy according to tumor hypoxia.
2026-05-05 | GSE241538 | GEO
Project description:Resistance to antiangiogenics is a major challenge in cancer therapy. These agents can either normalize or exacerbate tumor vascular abnormality and hypoxia. The mechanisms of resistance remain unclear in the latter setting. By integrating data from mouse models and clinical trials, we show that hypoxia-inducing anti-VEGF therapy upregulates programmed cell death ligand 1 (PD-L1), yet fails to sensitize tumors to PD-L1 blockade. Mechanistically, early hypoxic stress triggers epithelial osteopontin (Spp1) production, which recruits monocytes and skews macrophages toward M2 states, suppressing T-cell cytotoxicity. Pharmacologic Spp1 depletion impedes the development of hypoxia, M2 infiltration, restores T-cell activity and enables synergy between antiangiogenics and anti-PD-L1. Genetic dissection – tumor-epithelial Spp1 knockout grafts and bone-marrow chimeras generated by lethal irradiation and reconstitution with Spp1-/- or wild-type hematopoietic donors – show that myeloid Spp1 contributes only marginally compared with epithelial Spp1. These findings identify Spp1 as a central mediator of resistance to hypoxia-inducing antiangiogenics, contribute to a comprehensive model of antiangiogenic resistance, and support Spp1-targeted strategies to personalize immuno/antiangiogenic therapy according to tumor hypoxia.
2026-05-05 | GSE241527 | GEO
Project description:Resistance to antiangiogenics is a major challenge in cancer therapy. These agents can either normalize or exacerbate tumor vascular abnormality and hypoxia. The mechanisms of resistance remain unclear in the latter setting. By integrating data from mouse models and clinical trials, we show that hypoxia-inducing anti-VEGF therapy upregulates programmed cell death ligand 1 (PD-L1), yet fails to sensitize tumors to PD-L1 blockade. Mechanistically, early hypoxic stress triggers epithelial osteopontin (Spp1) production, which recruits monocytes and skews macrophages toward M2 states, suppressing T-cell cytotoxicity. Pharmacologic Spp1 depletion impedes the development of hypoxia, M2 infiltration, restores T-cell activity and enables synergy between antiangiogenics and anti-PD-L1. Genetic dissection – tumor-epithelial Spp1 knockout grafts and bone-marrow chimeras generated by lethal irradiation and reconstitution with Spp1-/- or wild-type hematopoietic donors – show that myeloid Spp1 contributes only marginally compared with epithelial Spp1. These findings identify Spp1 as a central mediator of resistance to hypoxia-inducing antiangiogenics, contribute to a comprehensive model of antiangiogenic resistance, and support Spp1-targeted strategies to personalize immuno/antiangiogenic therapy according to tumor hypoxia.
2026-05-05 | GSE243273 | GEO
Project description:Osteopontin links acquired resistance to hypoxia-inducing antiangiogenics with refractoriness to anti-PD-L1 agents in breast cancer
| PRJNA1455483 | ENA
Project description:Osteopontin links acquired resistance to hypoxia-inducing antiangiogenics with refractoriness to anti-PD-L1 agents in breast cancer
| PRJNA1457066 | ENA
Project description:Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1) have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy. Despite the inherent advantages of small-molecule inhibitors over antibodies, the discovery of small-molecule inhibitors has fallen behind that of antibody drugs. Based on docking studies between small molecule inhibitor and PD-L1 protein, changing the chemical linker of inhibitor from a flexible chain to an aromatic ring may improve its binding capacity to PD-L1 protein, which was not reported before. A series of novel phthalimide derivatives from structure-based rational design was synthesized. P39 was identified as the best inhibitor with promising activity, which not only inhibited PD-1/PD-L1 interaction (IC50 = 8.9 nmol/L), but also enhanced killing efficacy of immune cells on cancer cells. Co-crystal data demonstrated that P39 induced the dimerization of PD-L1 proteins, thereby blocking the binding of PD-1/PD-L1. Moreover, P39 exhibited a favorable safety profile with a LD50 > 5000 mg/kg and showed significant in vivo antitumor activity through promoting CD8+ T cell activation. All these data suggest that P39 acts as a promising small chemical inhibitor against the PD-1/PD-L1 axis and has the potential to improve the immunotherapy efficacy of T-cells.
| S-EPMC9764071 | biostudies-literature
Project description:Immune-checkpoint blockade has revolutionized cancer treatment. However, most patients do not respond to single-agent therapy. Combining checkpoint inhibitors with other immune-stimulating agents increases both efficacy and toxicity due to systemic T-cell activation. Protease-activatable antibody prodrugs, known as Probody therapeutics (Pb-Tx), localize antibody activity by attenuating capacity to bind antigen until protease activation in the tumor microenvironment. Herein, we show that systemic administration of anti-programmed cell death ligand 1 (anti-PD-L1) and anti-programmed cell death protein 1 (anti-PD-1) Pb-Tx to tumor-bearing mice elicited antitumor activity similar to that of traditional PD-1/PD-L1-targeted antibodies. Pb-Tx exhibited reduced systemic activity and an improved nonclinical safety profile, with markedly reduced target occupancy on peripheral T cells and reduced incidence of early-onset autoimmune diabetes in nonobese diabetic mice. Our results confirm that localized PD-1/PD-L1 inhibition by Pb-Tx can elicit robust antitumor immunity and minimize systemic immune-mediated toxicity. These data provide further preclinical rationale to support the ongoing development of the anti-PD-L1 Pb-Tx CX-072, which is currently in clinical trials.
| S-EPMC9414278 | biostudies-literature
Project description:Blockade of the programmed death 1 (PD-1)/ programmed death ligand 1 (PD-L1) immune checkpoint could increase antitumor immunotherapy for multiple types of cancer, but the response rate of patients is about 10%-40%. Peroxisome proliferator activated receptor γ (PPARγ) plays an important role in regulating cell metabolism, inflammation, immunity, and cancer progression, while the mechanism of PPARγ on cancer cell immune escape is still unclear. Here we found that PPARγ expression exhibits a positive correlation with activation of T cells in non-small-cell lung cancer (NSCLC) by clinical analysis. Deficiency of PPARγ promoted immune escape of NSCLC by inhibiting T-cell activity, which was associated with increased PD-L1 protein level. Further analysis showed that PPARγ reduced PD-L1 expression independent of its transcriptional activity. PPARγ contains the microtubule-associated protein 1A/1B-light chain 3 (LC3) interacting region motif, which acts as an autophagy receptor for PPARγ binding to LC3, leading to degradation of PD-L1 in lysosomes, which in turn suppresses NSCLC tumor growth by increasing T-cell activity. These findings suggest that PPARγ inhibits the tumor immune escape of NSCLC by inducing PD-L1 autophagic degradation.
| S-EPMC10323095 | biostudies-literature