PD-L1 regulates dendritic cell ferroptosis during immunogenic chemotherapy
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ABSTRACT:
PROVIDER: PRJNA876931 | ENA |
REPOSITORIES: ENA
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Project description:Dendritic cells (DCs) express high levels of PD-L1 in the tumor microenvironment and draining lymph nodes. Here, we explore the roles of PD-L1 signaling during immunogenic chemotherapy. DC-conditional PD-L1 knockout mice were inoculated with MC38-OVA tumors and treated with doxorubicin. T cells were isolated from draining lymph node for single cell RNA sequencing.
2024-09-23 | GSE223509 | GEO
Project description:PD-L1 regulates dendritic cell ferroptosis during immunogenic chemotherapy [scRNA-seq]
| PRJNA926616 | ENA
Project description:Dendritic cells (DCs) express high levels of PD-L1 in the tumor microenvironment. However, the physiological functions of PD-L1 on DCs remain incompletely understood. Here, we explored the roles of PD-L1 signaling in dendritic cells. PD-L1 was knocked out in DC2.4 cells and transcriptional profiles were analyzed.
2024-09-23 | GSE212711 | GEO
Project description:Despite the remarkable success of programmed death 1/PD-L1 inhibition in tumor therapy, only a minority of patients benefits from it. Previous studies suggest the anti-PD-1 treatment failure may attribute to the intrinsic functions of PD-L1 in cancer cells. Here, we established a genome-wide CRISPR synthetic lethality screen to systematic explore the PD-L1 intrinsic function in head and neck squamous cell carcinoma (HNSCC) cells. Ferroptosis related genes were identified to be essential for PD-L1 deficient cell viability. Genetic and pharmacological induction of ferroptosis accelerated cell death in PD-L1 knockout cells. PD-L1 knockout cells were also highly susceptible to immunogenic ferroptosis in vitro and in vivo. Mechanistically, nuclear PD-L1 transcriptionally activated SOD2 expression to maintain redox homeostasis. Importantly, the lower ROS and ferroptosis were observed in HNSCC patients with the higher expression of PD-L1. In summary, our study illustrates that PD-L1 confers ferroptosis resistance by activating SOD2-meidated redox homeostasis in HNSCC cells, indicating an enhanced therapeutic effect can be achieved by targeting the intrinsic PD-L1 function during immunotherapy.
2024-07-08 | GSE268534 | GEO
Project description:Despite the remarkable success of programmed death 1/PD-L1 inhibition in tumor therapy, only a minority of patients benefits from it. Previous studies suggest the anti-PD-1 treatment failure may attribute to the intrinsic functions of PD-L1 in cancer cells. Here, we established a genome-wide CRISPR synthetic lethality screen to systematic explore the PD-L1 intrinsic function in head and neck squamous cell carcinoma (HNSCC) cells. Ferroptosis related genes were identified to be essential for PD-L1 deficient cell viability. Genetic and pharmacological induction of ferroptosis accelerated cell death in PD-L1 knockout cells. PD-L1 knockout cells were also highly susceptible to immunogenic ferroptosis in vitro and in vivo. Mechanistically, nuclear PD-L1 transcriptionally activated SOD2 expression to maintain redox homeostasis. Importantly, the lower ROS and ferroptosis were observed in HNSCC patients with the higher expression of PD-L1. In summary, our study illustrates that PD-L1 confers ferroptosis resistance by activating SOD2-meidated redox homeostasis in HNSCC cells, indicating an enhanced therapeutic effect can be achieved by targeting the intrinsic PD-L1 function during immunotherapy.
2024-07-08 | GSE268533 | GEO
Project description:Blocking the PD-1/PD-L1 immunosuppressive pathway has shown promise in the treatment of certain cancers including melanoma. This study investigates differences in the gene expression profiles of human melanomas that do or do not display the immunosuppressive protein PD-L1. Further understanding of genes expressed within the tumor microenvironment of PD-L1+ tumors may lead to improved rationally designed treatments. Gene expression profiling was performed on total RNA extracted by laser capture microdissection from 11 archived formalin-fixed paraffin-embedded (FFPE) melanoma specimens, 5 of which were PD-L1 positive and 6 PD-L1 negative. Details of the design, and the gene signatures found are given in the paper associated with this GEO Series: Janis M. Taube, Geoffrey D. Young, Tracee L. McMiller, Shuming Chen, January T. Salas, Theresa S. Pritchard, Haiying Xu, Alan K. Meeker, Jinshui Fan, Chris Cheadle, Alan E. Berger, Drew M. Pardoll, and Suzanne L. Topalian, Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade, Clin Cancer Res 2015, in press.
2015-05-01 | E-GEOD-65041 | biostudies-arrayexpress
Project description:BackgroundChemotherapy is currently evaluated in order to enhance the efficacy of immune checkpoint blockade (ICB) therapy in colorectal cancer. However, the mechanisms by which these drugs could synergize with ICB remains unclear. The impact of chemotherapy on the PD-1/PD-L1 pathway and the resulting anticancer immune responses was assessed in two mouse models of colorectal cancer and validated in tumor samples from metastatic colorectal cancer patients that received neoadjuvant treatment. We demonstrated that 5-Fluorouracil plus Oxaliplatin (Folfox) drove complete tumor cure in mice when combined to anti-PD-1 treatment, while each monotherapy failed. This synergistic effect relies on the ability of Folfox to induce tumor infiltration by activated PD-1+ CD8 T cells in a T-bet dependent manner. This effect was concomitantly associated to the expression of PD-L1 on tumor cells driven by IFN-? secreted by PD-1+ CD8 T cells, indicating that Folfox triggers tumor adaptive immune resistance. Finally, we observed an induction of PD-L1 expression and high CD8 T cell infiltration in the tumor microenvironment of colorectal cancer patients treated by Folfox regimen. Our study delineates a molecular pathway involved in Folfox-induced adaptive immune resistance in colorectal cancer. The results strongly support the use of immune checkpoint blockade therapy in combination with chemotherapies like Folfox.
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Project description:The higher immunogenicity of tumors usually predicts favorable therapeutic responses. Tumor antigens dominate the immunogenic character within tumors. We investigated if there was a targetable tumor antigen during immunogenic chemotherapy within lung cancer. Chemotherapy-induced immunogenic senescence was demonstrated using a multi-marker, three-step workflow and RNA-sequencing data. The ability of anti-lung-specific X protein (LUNX) antibody to suppress the survival of senescent lung cancer cells was evaluated in vitro and in vivo using real-time cytotoxicity analysis and xenograft mouse models, respectively. The induction of cellular senescence by immunogenic chemotherapy boosted cell-surface shuttling of LUNX and enhanced the immunogenic features of senescent tumor cells, which sensitized lung cancer cells to anti-LUNX antibody-mediated therapy and contributed to tumor suppression. The immunogenic senescence-mediated anti-tumor response was triggered by the direct action of antibody on tumor cells, strengthened by natural-killer cells through an antibody-dependent cell-mediated cytotoxicity response and, ultimately, led to tumor control. Our findings suggest that LUNX is a lung cancer targetable-immunogenic antigen. The proportion of lung cancers responding to LUNX-targeting therapy could be expanded substantially by immunogenic chemotherapy that induces senescence-associated translocation of LUNX to the plasma membrane.
2024-10-03 | GSE185207 | GEO
Project description:The higher immunogenicity of tumors usually predicts favorable therapeutic responses. Tumor antigens dominate the immunogenic character within tumors. We investigated if there was a targetable tumor antigen during immunogenic chemotherapy within lung cancer. Chemotherapy-induced immunogenic senescence was demonstrated using a multi-marker, three-step workflow and RNA-sequencing data. The ability of anti-lung-specific X protein (LUNX) antibody to suppress the survival of senescent lung cancer cells was evaluated in vitro and in vivo using real-time cytotoxicity analysis and xenograft mouse models, respectively. The induction of cellular senescence by immunogenic chemotherapy boosted cell-surface shuttling of LUNX and enhanced the immunogenic features of senescent tumor cells, which sensitized lung cancer cells to anti-LUNX antibody-mediated therapy and contributed to tumor suppression. The immunogenic senescence-mediated anti-tumor response was triggered by the direct action of antibody on tumor cells, strengthened by natural-killer cells through an antibody-dependent cell-mediated cytotoxicity response and, ultimately, led to tumor control. Our findings suggest that LUNX is a lung cancer targetable-immunogenic antigen. The proportion of lung cancers responding to LUNX-targeting therapy could be expanded substantially by immunogenic chemotherapy that induces senescence-associated translocation of LUNX to the plasma membrane.
2024-10-03 | GSE185208 | GEO
Project description:Lung cancer is a major global health problem, as it is the leading cause of cancer- related deaths worldwide. Non-small-cell lung cancer (NSCLC), the most common form, is a heterogeneous disease with adenocarcinoma and squamous cell carcinoma being the predominant subtypes. Immune-inhibiting interaction of Programmed cell death-ligand 1 (PD-L1) with programmed cell death-protein 1 (PD-1) causes checkpoint mediated immune evasion and is, accordingly, an important therapeutic target in cancer. In NSCLC, improved understanding of PD-1/PD-L1 checkpoint blockade-responsive biology is warranted. We aimed to identify the landscape of immune cell infiltration in primary lung adeno- carcinoma (LUAD) in the context of tumor PD-L1 expression and the extent of immune infiltration (“hot” vs. “cold” phenotype). Therefore, the study comprises LUAD cases (n=138) with “hot” and “cold” tumor immune phenotype and positive and negative tumor PD-L1 expression, respectively. Tumor samples were immunohistochemically analyzed for expression of PD-L1, CD4 and CD8 and further analyzed on transcriptomic level by Nanostring nCouter Pan Cancer Immune Profiling Panel. We detected significantly differentially expressed genes associated with PD-L1 positive and “hot” versus PD-L1 negative and “cold” phenotype. The presented study illustrates novel aspects of PD-L1 regulation, with potential biological relevance, as well as relevance for immunotherapy response stratification.
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