USP5 facilitates non-small cell lung cancer progression through stabilization of PD-L1
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ABSTRACT:
SUBMITTER: Pan J
PROVIDER: S-EPMC8571306 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Lung cancer is the leading cause of cancer death in males and the second leading cause of death in females worldwide. Non-small-cell lung cancer (NSCLC) is the main pathological type of lung cancer, and most newly diagnosed NSCLC patients cannot undergo surgery because the disease is already locally advanced or metastatic. Despite chemoradiotherapy and targeted therapy improving clinical outcomes, overall survival remains poor. Immune checkpoint blockade, especially blockade of programmed death-1 (PD-1) receptor and its ligand PD-L1, achieved robust responses and improved survival for patients with locally advanced/metastatic NSCLC in preclinical and clinical studies. However, with regard to PD-1/PD-L1 checkpoint blockade as monotherapy or in combination with other antitumor therapies, such as chemotherapy, radiotherapy (including conventional irradiation and stereotactic body radiotherapy), and target therapy, there are still many unknowns in treating patients with NSCLC. Despite this limited understanding, checkpoint blockade as a novel therapeutic approach may change the treatment paradigm of NSCLC in the future. Here we review the main results from completed and ongoing studies to investigate the feasibility of PD-1/PD-L1 inhibitors, as monotherapy or combinatorial agents in patients with locally advanced and metastatic NSCLC, and explore optimal strategy in such patients.
| S-EPMC4741366 | biostudies-other
Project description:Programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) pathway blockade is a promising new cancer therapy. Although PD-1/PD-L1 treatment has yielded clinical benefits in several types of cancer, further studies are required to clarify predictive biomarkers for drug efficacy and to understand the fundamental mechanism of PD-1/PD-L1 interaction between host and tumor cells. Here, we show that exosomes derived from lung cancer cells express PD-L1 and play a role in immune escape by reducing T-cell activity and promoting tumor growth. The abundance of PD-L1 on exosomes represented the quantity of PD-L1 expression on cell surfaces. Exosomes containing PD-L1 inhibited interferon-gamma (IFN-?) secretion by Jurkat T cells. IFN-? secretion was restored by PD-L1 knockout or masking on the exosomes. Both forced expression of PD-L1 on cells without PD-L1 and treatment with exosomes containing PD-L1 enhanced tumor growth in vivo. PD-L1 was present on exosomes isolated from the plasma of patients with non-small cell lung cancer, and its abundance in exosomes was correlated with PD-L1 positivity in tumor tissues. Exosomes can impair immune functions by reducing cytokine production and inducing apoptosis in CD8+ T cells. Our findings indicate that tumor-derived exosomes expressing PD-L1 may be an important mediator of tumor immune escape.
| S-EPMC6802663 | biostudies-literature
Project description:In recent years, immunotherapy has revolutionized and changed the standard of care in patients with advanced non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors, fundamentally those that act by blocking the programmed cell death receptor-1 (PD-1) and its ligand the programmed cell death ligand-1 (PD-L1) have emerged as novel treatment strategies in NSCLC, demonstrating undoubted superiority over chemotherapy in terms of efficacy. Several of these immune checkpoint modulators have recently gained regulatory approval for the treatment of advanced NSCLC, such as nivolumab, atezolizumab and pembrolizumab in first-line (only the latter) and second-line settings, and more recently, durvalumab as maintenance after chemoradiotherapy in locally advanced disease. There is consensus that PD-L1 expression on tumor cells predicts responsiveness to PD-1 inhibitors in several tumor types. Hence PD-L1 expression evaluated by immunohistochemistry (IHC) is currently used as a clinical decision-making tool to support the use of checkpoint inhibitors in NSCLC patients. However, the value of PD-L1 as the 'definitive' biomarker is controversial as its testing is puzzled by multiple unsolved issues such as the use of different staining platforms and antibodies, the type of cells in which PD-L1 is assessed (tumor versus immune cells), thresholds used for PD-L1-positivity, or the source and timing for sample collection. Therefore, newer biomarkers such as tumor mutation burden and neoantigens as well as biomarkers reflecting host environment (microbiome) or tumor inflamed microenvironment (gene expression signatures) are being explored as more reliable and accurate alternatives to IHC for guiding treatment selection with checkpoint inhibitors in NSCLC.
| S-EPMC5898658 | biostudies-literature
Project description:ObjectivesLong non-coding RNAs (lncRNAs) have been demonstrated as crucial regulators in cancer, but whether they are involved in the immune response of cancer cells remains largely undiscovered. GATA3-AS1 is a novel lncRNA that was upregulated in breast cancer (BC) according to online databases. However, its role in triple-negative breast cancer (TNBC) was elusive.MethodsGATA3-AS1 expression in BC tissues and adjacent normal tissues was obtained from online databases. Loss-of-function assays were designed and conducted to verify the functional role of GATA3-AS1 in TNBC cells. Bioinformatic analysis and mechanism experiments were applied to explore the downstream molecular mechanism of GATA3-AS1. Similarly, the upstream mechanism which led to the upregulation of GATA3-AS1 in TNBC cells was also investigated.ResultsGATA3-AS1 was markedly overexpressed in TNBC tissues and cells. Knockdown of GATA3-AS1 suppressed TNBC cell growth and enhanced the resistance of TNBC cells to immune response. GATA3-AS1 induced the deubiquitination of PD-L1 through miR-676-3p/COPS5 axis. GATA3-AS1 destabilized GATA3 protein by promoting GATA3 ubiquitination.ConclusionGATA3-AS1 contributed to TNBC progression and immune evasion through stabilizing PD-L1 protein and degrading GATA3 protein, offering a new target for the treatment of TNBC.
| S-EPMC7507373 | biostudies-literature
Project description:Treatment of advanced (metastatic) non-small-cell lung cancer (NSCLC) is currently mainly based on immunotherapy with antibodies against PD-1 or PD-L1, alone, or in combination with chemotherapy. In locally advanced NSCLC and in early resected stages, immunotherapy is also employed. Tumor PD-L1 expression by immunohistochemistry is considered the standard practice. Response rate is low, with median progression free survival very short in the vast majority of studies reported. Herein, numerous biological facets of NSCLC are described involving driver genetic lesions, mutations ad fusions, PD-L1 glycosylation, ferroptosis and metabolic rewiring in NSCLC and lung adenocarcinoma (LUAD). Novel concepts, such as immune-transmitters and the effect of neurotransmitters in immune evasion and tumor growth, the nascent relevance of necroptosis and pyroptosis, possible new biomarkers, such as gasdermin D and gasdermin E, the conundrum of K-Ras mutations in LUADs, with the growing recognition of liver kinase B1 (LKB1) and metabolic pathways, including others, are also commented. The review serves to charter diverse treatment solutions, depending on the main altered signaling pathways, in order to have effectual immunotherapy. Tumor PDCD1 gene (encoding PD-1) has been recently described, in equilibrium with tumor PD-L1 (encoded by PDCD1LG1). Such description explains tumor hyper-progression, which has been reported in several studies, and poises the fundamental criterion that IHC PD-L1 expression as a biomarker should be revisited.
| S-EPMC7352732 | biostudies-literature
Project description:BackgroundProgrammed cell death ligand-1 (PD-L1) and ligand-2 (PD-L2) interaction with programmed cell death protein-1 (PD-1) represent an immune-inhibiting checkpoint mediating immune evasion and is, accordingly, an important target for blockade-based immunotherapy in cancer. In non-small-cell lung cancer (NSCLC), improved understanding of PD-1 checkpoint blockade-responsive biology and identification of biomarkers for prediction of a clinical response to immunotherapy is warranted. Thus, in the present study, we systematically described PD-L1 and PD-L2 expression correlated genes in NSCLC.MethodsWe performed comparative retrospective analyses to identify PD-L1 and PD-L2 mRNA expression correlated genes in NSCLC. For this, we examined available datasets from the cancer cell line encyclopedia (CCLE) project lung non-small-cell (Lung_NSC) and the cancer genome atlas (TCGA) projects lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC).ResultsAnalysis of the CCLE dataset Lung_NSC identified expression correlation between PD-L1 and PD-L2. Moreover, we identified expression correlation between 489 genes and PD-L1, 191 genes and PD-L2, and 111 genes for both. PD-L1 and PD-L2 also expression correlated in TCGA datasets LUAD and LUSC. In LUAD, we identified expression correlation between 257 genes and PD-L1, 914 genes and PD-L2, and 211 genes for both. In LUSC, we identified expression correlation between 26 genes and PD-L1, 326 genes and PD-L2, and 13 genes for both. Only a few genes expression correlated with PD-L1 and PD-L2 across the CCLE and TCGA datasets. Expression of Interferon signaling-involved genes converged in particular with the expression correlated genes for PD-L1 in Lung_NSC, for PD-L2 in LUSC, and for both PD-L1 and PD-L2 in LUAD. In LUSC, PD-L1, and to a lesser extent PD-L2, expression correlated with chromosome 9p24 localized genes, indicating a chromosome 9p24 topologically associated domain as an important driver of in particular LUSC PD-L1 expression. Expression correlation analyses of the PD-L1 and PD-L2 receptors programmed cell death protein-1 (PD-1), Cluster of differentiation 80 (CD80), and Repulsive guidance molecule B (RGMB) showed that PD-1 and CD80 expression correlated with both PD-L1 and PD-L2 in LUAD. CD80 expression correlated with PD-L2 in LUSC.ConclusionsWe present gene signatures associated with PD-L1 and PD-L2 mRNA expression in NSCLC which could possess importance in relation to understand PD-1 checkpoint blockade-responsive biology and development of gene signature based biomarkers for predicting clinical responses to immunotherapy.
| S-EPMC6545701 | biostudies-literature
Project description:Inhibition of the PD-1/PD-L1 pathway may induce anticancer immune responses in non-small cell lung cancer (NSCLC). Two PD-L1 immunohistochemistry (IHC) assays have been approved as companion diagnostic tests for therapeutic anti-PD-1 antibodies. However, many aspects of PD-L1 prevalence and association with genetically defined subtypes have not been addressed systematically. Here, we analyzed PD-L1 expression in 436 genetically annotated NSCLC specimens enriched for early stages using PD-L1 antibody 5H1. Expression of PD-L1 was detected in the tumor cells (TC) (34% of cases) and in associated immune cells (IC) (49%) across all stages of NSCLC, either alone or in combination. PD-L1 IHC-positive TC, but not IC showed significantly higher PD-L1 RNA expression levels. Expression in TC was associated with TP53, KRAS and STK11 mutational status in adenocarcinomas (AD) and with NFE2L2 mutations in squamous cell carcinomas (SQ). No correlations with histological subtype, clinical characteristics and overall survival were found. The presence of PD-L1-positive IC was significantly associated with patients' smoking status in AD. The findings are in agreement with the emerging concept that tumors with high mutational burden are more likely to benefit from immunotherapy, since TP53 and KRAS mutations are linked to smoking, increased numbers of somatic mutations and expression of neoantigens. Current clinical studies focus on stage IIIB and IV NSCLC; however, PD-L1 expression occurs in earlier stages and might be a predictive biomarker in clinical trials testing (neo-) adjuvant strategies.
| S-EPMC4910698 | biostudies-other
Project description:Currently, immunotherapy has shown great efficacy in clinical trials, and monoclonal antibodies directed against immune checkpoint PD-1/PD-L1 have shown encouraging results in first-line or second-line treatment of non-small cell lung cancer patients. Meanwhile, anti-PD-1/PD-L1 immune checkpoint drugs combined with other treatments, such as chemotherapy, targeted therapy as well as anti-CTLA-4 checkpoint therapy, are considered an attractive treatment with higher efficacy. However, toxicity associated with PD-1/PD-L1 blockade is worth attention. Understanding the adverse effects caused by anti-PD-1/PD-L1 immunosuppressive agents is vital to guide the clinical rational use of drug. In this review, we summarized the adverse effects that occurred during the clinical use of anti-PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer and discussed how to effectively manage and respond to these adverse reactions.
| S-EPMC7531287 | biostudies-literature
Project description:BackgroundAgents targeting programmed death-1 receptor (PD-1) and its ligand (PD-L1) are showing promising results in non-small-cell lung cancer (NSCLC). It is unknown whether PD-1/PD-L1 are differently expressed in oncogene-addicted NSCLC.MethodsWe analysed a cohort of 125 NSCLC patients, including 56 EGFR mutated, 29 KRAS mutated, 10 ALK translocated and 30 EGFR/KRAS/ALK wild type. PD-L1 and PD-1 expression were assessed by immunohistochemistry. All cases with moderate or strong staining (2+/3+) in >5% of tumour cells were considered as positive.ResultsPD-1 positive (+) was significantly associated with current smoking status (P=0.02) and with the presence of KRAS mutations (P=0.006), whereas PD-L1+ was significantly associated to adenocarcinoma histology (P=0.005) and with presence of EGFR mutations (P=0.001). In patients treated with EGFR tyrosine kinase inhibitors (N=95), sensitivity to gefitinib or erlotinib was higher in PD-L1+ vs PD-L1 negative in terms of the response rate (RR: P=0.01) time to progression (TTP: P<0.0001) and survival (OS: P=0.09), with no difference in PD1+ vs PD-1 negative. In the subset of 54 EGFR mutated patients, TTP was significantly longer in PD-L1+ than in PD-L1 negative (P=0.01).ConclusionsPD-1 and PD-L1 are differentially expressed in oncogene-addicted NSCLC supporting further investigation of specific checkpoint inhibitors in combination with targeted therapies.
| S-EPMC4453606 | biostudies-literature
Project description:Immune-checkpoint inhibitors (ICI) have transformed oncological therapy. Up to 20% of all non-small cell lung cancers (NSCLCs) show durable responses upon treatment with ICI, however, robust markers to predict therapy response are missing. Here we show that blood platelets interact with lung cancer cells and that PD-L1 protein is transferred from tumor cells to platelets in a fibronectin 1, integrin α5β1 and GPIbα-dependent manner. Platelets from NSCLC patients are found to express PD-L1 and platelet PD-L1 possess the ability to inhibit CD4 and CD8 T-cells. An algorithm is developed to calculate the activation independent adjusted PD-L1 payload of platelets (pPD-L1Adj.), which is found to be superior in predicting the response towards ICI as compared to standard histological PD-L1 quantification on tumor biopsies. Our data suggest that platelet PD-L1 reflects the collective tumor PD-L1 expression, plays important roles in tumor immune evasion and overcomes limitations of histological quantification of often heterogeneous intratumoral PD-L1 expression.
| S-EPMC8636618 | biostudies-literature