Immune suppressive landscape in the human non-small cell lung cancer microenvironment
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PROVIDER: PRJNA813604 | ENA |
REPOSITORIES: ENA
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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:Immune suppressive landscape in a human esophageal squamous cell carcinoma microenvironment
| PRJNA606979 | ENA
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:Properly applying current immunotherapies or developing novel therapeutic strategies relies on a comprehensive understanding of the immune elements of the tumor microenvironment (TME). In this study, we aim to map at single-cell resolution the immune landscape of esophagus squamous cell carcinoma (ESCC), a common, aggressive, but understudied cancer of the gastrointestinal tract. We obtained a detailed immune cell atlas of the ESCC-associated transcriptome from a total of 80,787 tumor-infiltrating immune cells. Significant intertumoral heterogeneity was found among individual ESSC tumors. Exhausted T cells, exhausted NK cells, regulatory T cells, alternatively activated macrophages, and tolerogenic dendritic cells were discovered as the dominant portions of the immune cells in the TME. Dysfunctional T cells were the major proliferative cell compartment among tumor-infiltrating immune cells. In addition, strong potential interactions of immune cells in tumors may contribute to the immunosuppressive status and the progress of tumor development; a six-gene signature, comprising IFNGR1, IFNGR2, IDO1, IL10, CD163, and CD274, were associated with ESCC survival. Our results provided a comprehensive characterization of tumor-infiltrating immune cells in ESCC, indicating that immunosuppression of various kinds was synchronously responsible for the failure of immunosurveillance in ESCC. Specifically targeting the immunosuppressive pathways could reverse the immune-suppressive status and reactivate anti-tumor immune responses in ESCC.
2020-10-19 | GSE145370 | GEO
Project description:We analyzed 40,799 single cells from nine samples and found that in EGFR-mutant LUAD, tumor cells generated an immunosuppressive microenvironment by releasing cytokines to attract suppressive immune cells such as myeloid-derived suppressor cells (MDSCs) directly or indirectly by interacting with macrophages, dendritic cells, or other cell types. By contrast, EGFR wild-type LUAD had a greater ability to recruit immunocompetent T cells such as TRMs and Th1 cells, thus driving a proinflammatory microenvironment.
2022-02-09 | GSE171145 | GEO
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:Cancer immunotherapy has revolutionized cancer treatment, and it relies heavily on the comprehensive understanding of the immune landscape of the tumor microenvironment (TME). Here, we obtain a detailed immune cell atlas of esophageal squamous cell carcinoma (ESCC) at single-cell resolution. Exhausted T and NK cells, regulatory T cells (Tregs), alternatively activated macrophages and tolerogenic dendritic cells are dominant in the TME. Transcriptional profiling coupled with T cell receptor (TCR) sequencing reveal lineage connections in T cell populations. CD8 T cells show continuous progression from pre-exhausted to exhausted T cells. While exhausted CD4, CD8 T and NK cells are major proliferative cell components in the TME, the crosstalk between macrophages and Tregs contributes to potential immunosuppression in the TME. Our results indicate several immunosuppressive mechanisms that may be simultaneously responsible for the failure of immuno-surveillance. Specific targeting of these immunosuppressive pathways may reactivate anti-tumor immune responses in ESCC.
| S-EPMC7722722 | biostudies-literature
Project description:TAZ facilitates breast tumor growth by promoting an immune-suppressive tumor microenvironment
| PRJNA1011907 | ENA
Project description:TGFß in the microenvironment induces a physiologically occurring immune-suppressive senescent state
| PRJNA924741 | ENA
Project description:The tumor microenvironment in brain metastases is characterized by high myeloid cell content with immune-suppressive and cancer-permissive functions. Moreover, brain metastases induce the recruitment of lymphocytes. Despite their presence, T cell-directed therapies fail to elicit effective anti-tumor immune responses. Here we seek to evaluate the applicability of radio-immunotherapy to modulate tumor immunity and overcome inhibitory effects that diminish anti-cancer activity. Radiotherapy-induced immune modulation resulted in an increase in cytotoxic T cell numbers and prevented the induction of lymphocyte-mediated immune suppression. Radio-immunotherapy led to significantly improved tumor control with prolonged median survival in experimental breast-to-brain metastases. However, long-term efficacy was not observed. Recurrent brain metastases showed accumulation of blood-borne PD-L1+ myeloid cells after radio-immunotherapy indicating the establishment of an immune-suppressive environment to counteract re-activated T cell responses. This finding was further supported by transcriptional analyses indicating a crucial role for monocyte-derived macrophages in mediating immune-suppression and regulating T cell function. Therefore, selective targeting of immune suppressive functions of myeloid cells is expected to be critical for improved therapeutic efficacy of radio-immunotherapy in brain metastases.
2021-02-12 | GSE164049 | GEO