PD-L1 alteration in lung cancer affects tumorigenicity lung tumors
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ABSTRACT:
PROVIDER: PRJNA720411 | ENA |
REPOSITORIES: ENA
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Project description:Cancer immunotherapy has focused on inhibitors of checkpoint proteins, such as Programmed Death Ligand 1 (PD-L1). Unlike RAS-mutated lung cancers, EGFR mutant tumors have generally low response to immunotherapy. Because treatment outcomes vary by EGFR allele, we assumed that intrinsic and microenvironmental factors are involved. Among all non-immunological signaling pathways we surveyed in patients’ datasets, EGFR signaling best associated with high PD-L1. Correspondingly, active EGFRs stabilized PD-L1’s transcripts and depleting PD-L1 severely inhibited EGFR-driven tumorigenicity and metastasis in mice. The underlying mechanisms involve recruitment of phospholipase C-g1 (PLC-g1) to a cytoplasmic motif of PD-L1, which enhances PLC-g1 activation by EGFR. Once stimulated, PLC-g1 activates calcium flux, RHO GTPases and protein kinase C, which promotes an aggressive phenotype. Furthermore, anti-PD-L1 antibodies can inhibit these intrinsic functions of PD-L1. Our results portray PD-L1 as a molecular amplifier of EGFR signaling and lay the foundation for understanding resistance of EGFR+ tumors to immunotherapy.
2021-04-08 | GSE171650 | GEO
Project description:Cancer cells express high levels of PD-L1, a ligand of the PD-1 receptor on T cells, allowing tumors to suppress T cell activity 1-3. Clinical trials utilizing monoclonal antibodies that disrupt the PD-1/PD-L1 immune checkpoint have yielded remarkable results, with PD-1 immunotherapy approved as a first-line therapy for human lung cancer patients 4-6. Despite significant progress in targeting this pathway, the mechanisms through which PD-L1 is upregulated in non-small cell lung cancer (NSCLC) and other tumor types remain incompletely understood. Here we used CRISPR-based screening to identify regulators of PDL1 in human lung cancer cells, revealing potent induction of PD-L1 levels upon disruption of the heme biosynthesis pathway. Impairment of heme production activates the integrated stress response (ISR), allowing bypass of inhibitory upstream open reading frames in the PD-L1 5¢ UTR, resulting in enhanced PD-L1 translation and suppression of anti-tumor immunity. We further demonstrated that ISR-dependent translation of PD-L1 requires the translation initiation factor EIF5B. EIF5B overexpression, which is frequent in human lung cancers and is associated with poor prognosis, is sufficient to induce PD-L1. These findings uncover a new mechanism of immune checkpoint activation and suggest novel targets for therapeutic intervention.
2020-02-01 | GSE129968 | GEO
Project description:Targeting checkpoint blockade to rescue exhausted regulatory T cells (Tregs) has become an essential immunotherapy strategy in treating cancer. Until now, the CD4+ Tregs and PD-1+CD8+ T cells were demonstrated to reduce immunogenic responses. In contrast, little is known about the PD-L1 graphic pattern and characteristics in CD8+ T cells. We performed two high-throughput analysis approaches on tumor-infiltrating CD8+ T cells in lung cancers. We discovered PD-L1+CD8+ T cells enriched in tumor lesions, localized with PD-1+CD8+ affected T cells, and owned regulatory functions. Moreover, tumor-derived IL-27 promoted the development of PD-L1+CD8+ T cells through STAT1/STAT3 signaling. Single-cell RNA sequencing data analysis further clarified the enrichment of PD-L1+CD8+ T cells related to the downregulation of adaptive immune response. Additionally, enrichment of this subset was correlated with poor survival of lung cancer patients. Our data collectively demonstrated that PD-L1+CD8+ T cells potentially become a prognostic biomarker in lung cancer.
2022-02-18 | GSE192591 | GEO
Project description:The identification of novel therapeutic strategies to overcome the intrinsic or acquired resistance to trametinib in mutant KRAS lung adenocarcinoma (LUAD) is a major challenge. This study analyzes the effects of trametinib in Id1, a key factor involved in the oncogenic KRAS pathway, and investigates the Id1 role in acquire resistance and synergy with immunotherapy in KRAS-driven LUAD. Restoring the antitumor immune response by blocking programmed-cell death protein 1 (PD-1) and programmed-cell death-ligand 1 (PD-L1) pathway represents a major breakthrough in non-small-cell lung cancer (NSCLC) treatment. Nevertheless, a high proportion of LUAD patients with KRAS alterations remain refractory to this therapy. Material and Methods: To explore whether MEK1/2 inhibition reduces Id1 expression, in vitro and in vivo experiments were conducted in KRAS-mutant NSCLC cells and murine models. RNAseq analysis was performed to elucidate the pathways involved in Id1 inhibition. Apoptosis and PD-L1 expression was measured by flow cytometry. Synergy of trametinib combined with anti-PD1 was investigated in KRAS-mutant LUAD mouse models. Results: Using preclinical syngeneic KRAS-mutant lung cancer mouse models, we demonstrate that trametinib synergizes with PD-1 blockade to reduce lung cancer progression and increase mice overall survival. This antitumor activity was linked to the degradation of Id1 via proteasome, and an enhanced INF-Y-mediated PD-L1 tumor cell expression in KRAS-mutant tumor cells. This effect required CD8+ T cells, boosted the intratumoral CD8+/Treg ratio, reducing the intratumoral Treg/CD4+ ratio. Conclusions: Our data may support the role of Id1 in the trametinib antitumoral effect, sustaining the mitogen-activated protein kinases (MAPK) signaling pathway involved in the trametinib acquired resistance cells and sensitizing KRAS-mutant lung tumors to PD-1 inhibitors, through PD-L1 overexpression.
2024-05-17 | GSE236258 | 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: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.
2021-09-27 | GSE180347 | GEO
Project description:Targeted gene expression on Lewis lung carcinoma (LLC) sorted MHC-IIlow macrophages (M2), Ly6Chigh inflammatory (IM) and Ly6Clow residential (RM) monocytes to investigate the effect of anti-PD-L1 mAb on specific myeloid subsets in the lung tumor microenvironment performed using the nCounter Myeloid Innate Immunity Panel by Nanostring .
2022-03-04 | GSE165517 | GEO
Project description:To systematically characterize anti-PD-1/PD-L1 immunotherapy-related changes in serum glycoproteins and discover novel biomarkers related to treatment response, we analyzed a series of sera samples from patients with metastatic lung squamous cell carcinoma (SCC) and lung adenocarcinoma (ADC), collected before and during ICIs treatment, with mass-spectrometry-based label-free quantification methodology.
2022-12-31 | PXD039141 | iProX
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.
2015-05-01 | GSE65041 | GEO
Project description:PRMT5 inhibition increases PD-L1 expression and immunoresistance in lung cancer
| PRJNA739472 | ENA