Profiling of DNA damage and repair pathways in small cell lung cancer reveals a suppressive role in the immune landscape.
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ABSTRACT:
SUBMITTER: Jin R
PROVIDER: S-EPMC8496044 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Small cell lung cancer (SCLC) is an aggressive malignancy that accounts for 14% of all lung cancer diagnoses. Despite decades of active research, treatment options for SCLC are limited and resistance to the few Food and Drug Administration (FDA) approved therapies develops rapidly. With no approved targeted agents to date, new therapeutic strategies are desperately needed. SCLC is characterized by high mutation burden, ubiquitous loss of TP53 and RB1, mutually exclusive amplification of MYC family members, thereby, high genomic instability. Studies in the past few years have demonstrated the potential of targeting the DNA damage response (DDR) pathway as a promising therapeutic strategy for SCLC. Inhibitors targeting DDR proteins have shown promise in preclinical models, and are under clinical investigation as single agents and in combination with cytotoxic therapies. Recent efforts to expand the therapeutic arsenal toward SCLC have focused in part on immune checkpoint inhibitors, such as agents targeting the receptor-ligand pair programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1). Clinical trials have confirmed activity of these agents in extensive stage (ES)-SCLC. However, while several patients had dramatic responses, overall response rates to immune checkpoint blockade (ICB) remain poor. As a result, there is an urgent need to develop rational combination therapies to enhance response rates to immunotherapy in SCLC. Identification of predictive biomarkers for patient stratification, identifying effective combinations to overcome adaptive resistance to DDR-targeted therapies and identifying strategies to enhance response to immunotherapy are areas of active investigation in SCLC.
| S-EPMC5835589 | biostudies-literature
Project description:Background: Lung cancer is the one of the malignant tumors with the highest morbidity and mortality in China and even the world. The overall five-year survival rate is about 20%, and most patients die of tumor metastasis. Non-small cell lung cancer (NSCLC) is the main pathologic type of lung cancer. The development and metastasis of tumor cells is influenced by the interaction with other cells in the environment. To explore the molecular expression spectrum of tumor and tumor microenvironment can provide clues for the mechanism of tumor progression, drug resistance and metastasis. The emergence of single cell ribonucleic acid sequencing (scRNA-seq) technology can explore the genomic and transcriptional characteristics of different tumor cells at the single cell resolution, which can reveal the molecular characteristics of individual cells and the relationship between individuals and the environment, thus making it possible to further understand the genesis and progression of NSCLC. Methods: ScRNA-seq (10X genomics) was used to detect single-cell transcriptomes in 2 patients with NSCLC, aiming to more accurately explore the effects of the transcriptome in a single cell on its function and the progression of NSCLC, and to find new cell subtypes or molecular targets for drug therapy. Results: The tumor tissue, distant normal tissue, and lymph node tissue of 2 patients with NSCLC were analyzed. A total of 43779 cells were analyzed, which were classified into epithelial cells, T lymphocytes, natural killer cells (NK cells), B lymphocytes, myeloid cells, endothelial cells, fibroblasts, and MAST cells. Tumor cells showed signature markers of epithelial (EPCAM, KRT7, KRT8, KRT18, CDH1, etc.) and tumor (KRT19, ENO2, SLC25A2, UBE2C, etc.) markers. Additionally, the acquired immunity is activated in the tumor microenvironment, while the innate immunity is exhausted. The proportion of B lymphocytes increases, and immunosuppressive tumor-infiltrating B cells (CD19+, MS4A1+, CD69+, CD27-, CR2-) are observed, which are capable of participating in the induction of exhausted regulatory T cells. The proportion of cytotoxic CD8+ T cells in T lymphocyte population decreases, and the number of exhausted regulatory T cells and exhausted follicular helper T cells increases. They all express LAG3+, TIGIT+, PDCD1+, CTLA4+, and other suppressive markers, showing a state of immunosuppression. High expression of WFDC2 in T cells has a significant effect on prognosis. NK cells show a state of depletion, not only in number, but also gradually transform into a less cytotoxic subtype (CD56+, CD16-). In addition, myeloid cells also play an important role in disrupting the anti-tumor immune response. Tumor associated macrophages (TAMs) and plasmacytoid dendritic cells (pDCs) are enriched in tumor tissue. TAMs highly express anti-inflammatory markers (APOE+, C1QA+, C1QB+) and proliferative markers (MKI67+, STMN1+, NUSAP1+), which are closely related to tumor progression and metastasis. TAMs show M2 type polarization of macrophages, which has a tumor promoting effect. At the same time, TAMs express monocyte markers, which may be transformed from monocyte derived macrophages. Macrophages highly express CXCL8, CCL2, and other genes, which participate in Toll-like receptor, NOD-like receptor signaling pathway, and have a significant impact on the prognosis. pDCs are immunosuppressive cells. The high expression of LILR family genes and GZMB in pDCs may lead to poor tumor antigen presentation of lung squamous cell carcinoma. Dendritic cells highly express NLRP3, IRF7, and other genes, which participate in C-type lectin receptor, Toll-like receptor, NOD-like receptor signaling pathway, and have a significant impact on the prognosis. In addition to the immune system, fibroblasts in the stroma also show characteristics of immunosuppressive cells. Enrichment of Cancer-associated fibroblasts (CAFs) in tumor can promote immunosuppression and tumor progression. Among them, a special subtype termed inflammatory CAFs is found, which participate in the process of extracellular matrix remodeling, angiogenesis, and cell migration, resulting in promoting tumor progression. Fibroblasts highly express FN1, TIMP1, and hub gene SPP1, which interact with macrophages, participate in PI3K-AKT pathway, and have a significant impact on the prognosis. Conclusions: NSCLC shows heterogeneous tumor microenvironment. A variety of immune cells and stromal cells together lead to immunosuppressive environment and promote the progression of tumor. This study enhances our understanding of molecular and cellular dynamics of NSCLC, and reveals potential diagnostic and therapeutic targets in tumor microenvironment.
2023-12-31 | GSE198099 | GEO
Project description:BackgroundAlmost all patients with small cell lung cancer (SCLC) relapse. The therapeutic options of relapsed SCLC are limited, and the clinical outcomes are poor. Thus, genomic profiling of relapsed SCLC patients may help to develop more effective therapeutic options.MethodsWe collected blood specimens and follow-up information from a consecutive cohort of 31 patients diagnosed with relapsed SCLC in Zhongnan Hospital, Wuhan University, between 2018 and 2019, to analyze the comprehensive genomic profiling, and to investigate the impact of genomic alterations on therapeutic options and survival.ResultsIn our cohort of relapsed SCLC, the median number of genomic alterations was 5 (range, 1-11) per sample. The majority of patients were defined as low tumor mutation burden (TMB; 83.9%) and microsatellite stability (MSS; 87.1%). Immune checkpoint inhibitors (ICIs)-based treatment still brought considerable progression-free survival (PFS; 4.93-20.27 months) for patients with low TMB and MSS. Additionally, the most frequent genetic alterations observed in relapsed SCLC were TP53 (77%) and RB1 (52%). Other genomic alterations of high frequency were breast cancer 2 (BRCA2) (32%), ataxia telangiectasia mutated (ATM) (13%), epidermal growth factor receptor (EGFR) (10%), Notch receptor 1 (NOTCH1) (10%), and Fanconi anemia complementation group A (FANCA) (10%), in turn. Finally, based on the survival of therapeutic strategies targeting potential mutation genes, the role of genotyping in relapsed SCLC was confirmed.ConclusionsOur studies first exhibited comprehensive genomic profiling of relapsed SCLC, identifying several candidate genes, and briefly analyzed the association of survival and genomic alterations. Our data from a small cohort of relapsed SCLC will benefit further exploration the potential targets or biomarkers.
| S-EPMC10797366 | biostudies-literature
Project description:Lung cancer is one of the most common causes of brain metastases and is always associated with poor prognosis. We investigated the immunophenotypes of primary lung tumors and paired brain metastases, as well as immunophenotypes in the synchronous group (patients with brain metastases upon initial diagnosis) and metachronous group (patients developed brain metastases during the course of their disease). RNA sequencing of eighty-six samples from primary lung tumors and paired brain metastases of 43 patients was conducted to analyze the tumor immune microenvironment. Our data revealed that matched brain metastases compared with primary lung tumors exhibited reduced tumor infiltrating lymphocytes (TILs), a higher fraction of neutrophils infiltration, decreased scores of immune-related signatures, and a lower proportion of tumor microenvironment immune type I (high PD-L1/high CD8A) tumors. Additionally, we found a poor correlation of PD-L1 expression between paired brain metastases and primary lung tumors. In addition, gene set enrichment analysis (GSEA) showed that some gene sets associated with the immune response were enriched in the metachronous group, while other gene sets associated with differentiation and metastasis were enriched in the synchronous group in the primary lung tumors. Moreover, the tumor immune microenvironment between paired brain metastases and primary lung tumors displayed more differences in the metachronous group than in the synchronous group. Our work illustrates that brain metastatic tumors are more immunosuppressed than primary lung tumors, which may help guide immunotherapeutic strategies for NSCLC brain metastases.
| S-EPMC8986255 | biostudies-literature
Project description:BackgroundDNA is subject to constant chemical modification and damage, which eventually results in variable mutation rates throughout the genome. Although detailed molecular mechanisms of DNA damage and repair are well understood, damage impact and execution of repair across a genome remain poorly defined.ResultsTo bridge the gap between our understanding of DNA repair and mutation distributions, we developed a novel method, AP-seq, capable of mapping apurinic sites and 8-oxo-7,8-dihydroguanine bases at approximately 250-bp resolution on a genome-wide scale. We directly demonstrate that the accumulation rate of apurinic sites varies widely across the genome, with hot spots acquiring many times more damage than cold spots. Unlike single nucleotide variants (SNVs) in cancers, damage burden correlates with marks for open chromatin notably H3K9ac and H3K4me2. Apurinic sites and oxidative damage are also highly enriched in transposable elements and other repetitive sequences. In contrast, we observe a reduction at chromatin loop anchors with increased damage load towards inactive compartments. Less damage is found at promoters, exons, and termination sites, but not introns, in a seemingly transcription-independent but GC content-dependent manner. Leveraging cancer genomic data, we also find locally reduced SNV rates in promoters, coding sequence, and other functional elements.ConclusionsOur study reveals that oxidative DNA damage accumulation and repair differ strongly across the genome, but culminate in a previously unappreciated mechanism that safeguards the regulatory and coding regions of genes from mutations.
| S-EPMC6284305 | biostudies-literature
Project description:For decades genotoxic therapy has been a mainstay in the treatment of cancer, based on the understanding that the deregulated growth and genomic instability that drive malignancy also confer a shared vulnerability. Although chemotherapy and radiation can be curative, only a fraction of patients benefit, while nearly all are subjected to the harmful side-effects. Drug repurposing, defined here as retooling existing drugs and compounds as chemo or radiosensitizers, offers an attractive route to identifying otherwise non-toxic agents that can potentiate the benefits of genotoxic cancer therapy to enhance the therapeutic ratio. This review seeks to highlight recent progress in defining cellular mechanisms of the DNA damage response including damage sensing, chromatin modification, DNA repair, checkpoint signaling, and downstream survival and death pathways, as a framework to determine which drugs and natural products may offer the most potential for repurposing as chemo- and/or radiosensitizers. We point to classical examples and recent progress that have identified drugs that disrupt cellular responses to DNA damage and may offer the greatest clinical potential. The most important next steps may be to initiate prospective clinical trials toward translating these laboratory discoveries to benefit patients.
| S-EPMC7483256 | biostudies-literature
Project description:The cancer immune microenvironment is of importance for the effectiveness of immunotherapy; however, its dysregulation is poorly understood. The MUC1-C oncoprotein is aberrantly overexpressed in non-small cell lung cancer (NSCLC) and has been linked to the induction of PD-L1. The present work investigated the effects of targeting MUC1-C in an immuno-competent MUC1 transgenic (MUC1.Tg) mouse model. We show that Lewis Lung Carcinoma cells expressing MUC1-C (LLC/MUC1) exhibit upregulation of PD-L1 and suppression of interferon-γ (IFN-γ). In studies of LLC/MUC1 cells growing in vitro and as tumors in MUC1.Tg mice, treatment with the MUC1-C inhibitor, GO-203, was associated with the downregulation of PD-L1 and induction of IFN-γ. The results further demonstrate that targeting MUC1-C results in enhanced effector function of CD8+ tumor-infiltrating lymphocytes (TILs) as evidenced by increased expression of the activation marker CD69, the degranulation marker CD107α, and granzyme B. Notably, targeting MUC1-C was also associated with marked increases in TIL-mediated killing of LLC/MUC1 cells. Analysis of gene expression data sets further showed that overexpression of MUC1 in NSCLCs correlates negatively with CD8, IFNG and GZMB, and that decreases in CD8 and IFNG are associated with poor clinical outcomes. These findings in LLC/MUC1 tumors and in NSCLCs indicate that MUC1-C→PD-L1 signaling promotes the suppression of CD8+ T-cell activation and that MUC1-C is a potential target for reprogramming of the tumor microenvironment.
| S-EPMC5599083 | biostudies-literature
Project description:BackgroundSmoking is the main risk factor for chronic obstructive pulmonary disease (COPD). Women with COPD who smoke experienced a higher risk of hospitalization and worse decline of lung function. Yet the mechanisms of these gender-related differences in clinical presentations in COPD remain unknown. The aim of our study is to identify proteins and molecular pathways associated with COPD pathogenesis, with emphasis on elucidating molecular gender difference.MethodWe employed shotgun isobaric tags for relative and absolute quantitation (iTRAQ) proteome analyses of bronchoalveolar lavage (BAL) cells from smokers with normal lung function (n = 25) and early stage COPD patients (n = 18). Multivariate modeling, pathway enrichment analysis, and correlation with clinical characteristics were performed to identify specific proteins and pathways of interest.ResultsMore pronounced alterations both at the protein- and pathway- levels were observed in female COPD patients, involving dysregulation of the FcγR-mediated phagocytosis-lysosomal axis and increase in oxidative stress. Alterations in pathways of the phagocytosis-lysosomal axis associated with a female-dominated COPD phenotype correlated well with specific clinical features: FcγR-mediated phagocytosis correlated with FEV1/FVC, the lysosomal pathway correlated with CT < -950 Hounsfield Units (HU), and regulation of actin cytoskeleton correlated with FEV1 and FEV1/FVC in female COPD patients. Alterations observed in the corresponding male cohort were minor.ConclusionThe identified molecular pathways suggest dysregulation of several phagocytosis-related pathways in BAL cells in female COPD patients, with correlation to both the level of obstruction (FEV1/FVC) and disease severity (FEV1) as well as emphysema (CT < -950 HU) in women.Trial registrationNo.: NCT02627872 , retrospectively registered on December 9, 2015.
| S-EPMC5842633 | biostudies-literature
Project description:Immunotherapy has evolved at a phenomenal pace in cancer therapeutics. This has primarily been fueled by the much perceived necessity to procure an alternative to current standard of care chemotherapy agents, owing to several concerns such as treatment-related toxicity and poor long-term survival associated with the same. The knowledge of various mechanisms involved in regulation of immune response to cancer cells has served a fundamental role in identifying key molecules through which immune cell activity may be modulated. This in-turn led to the development of immune-checkpoint inhibitors. Presently, lung cancer is among the most enthusiastically investigated targets for treatment with immune-checkpoint inhibitors. Encouraging results with initial trials have now translated to attempts directed at further enhancement of outcomes through various strategies. Herein, we shall present a critical assessment of data from pivotal trials that led to the Food and Drug Administration (FDA) approval of various immune-checkpoint inhibitors and also discuss novel strategies that may potentially yield outcomes superior to standard of care chemotherapy in patients diagnosed with advanced non-small cell lung cancer (NSCLC).
| S-EPMC5890048 | biostudies-literature
Project description:The profiling of the tumor immune microenvironment (TIME) is critical for guiding immunotherapy strategies. However, how the composition of the immune landscape affects the tumor progression of gastric cancer (GC) is ill-defined. Here, we used mass cytometry to perform simultaneous in-depth immune profiling of the tumor, adjacent tissues, and blood cells from GC patients and revealed a unique GC tumor-immune signature, where CD8+ T cells were present at a lower frequency in tumor tissues compared to adjacent tissues, whereas regulatory T cells and tumor-associated macrophages (TAMs) were significantly increased, indicating strong suppressive TIME in GC. Incorporated with oncogenic genomic traits, we found that the unique immunophenotype was interactively shaped by a specific GC gene signature across tumor progression. Earlier-stage GC lesions with IFN signaling enrichment harbored significantly altered T-cell compartments while advanced GC featured by metabolism signaling activation was accumulated by TAMs. Interestingly, PD-1 expression on CD8+ T cells was relatively higher in earlier-stage GC patients, indicating that these patients may derive more benefits from PD-1 inhibitors. The dynamic properties of diverse immune cell types revealed by our study provide new dimensions to the immune landscape of GC and facilitate the development of novel immunotherapy strategies for GC patients.
| S-EPMC9304688 | biostudies-literature