Immune Microenvironment
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2021 ◽  
Vol 2021 ◽  
pp. 1-16
Jiahang Song ◽  
Shuming Zhang ◽  
Yuanyuan Sun ◽  
Junjie Gu ◽  
Ziqi Ye ◽  

Purpose. Radiotherapy resistance is now recognized as the major obstacle to the effective therapeutic management of non-small-cell lung cancer (NSCLC). As a single biomarker has limited effect in stratifying NSCLC patients, this research aimed to identify long non-coding RNAs (lncRNAs) correlated with radiotherapy response to ameliorate forecast of NSCLC prognosis. Methods. In a cohort of NSCLC patients with radiotherapy history (n = 96) from TCGA, genetic data of lncRNA expression profiling were performed. To identify radioresponse-related lncRNA sets which dysregulated significantly between radiosensitive (RS) and radioresistant (RR) groups, differential expression analysis was carried out. Cox relative regression was implemented to set up a radioresponse-related risk model. Moreover, we adopted survival analysis to measure the predictive potentiality of the prognosis model. Results. Four radioresponse-related lncRNAs (CASC19, LINC01977, LINC02471, and MAGI2-AS3) were screened to create a prognostic signature. Then, we described a lncRNA signature-based regulatory network and explored the correlation of the immune microenvironment and the signature. Additionally, in vitro assays uncovered inhibition of LINC01977 weakened radioresistance of NSCLC cells. Conclusion. We provided a novel radioresponse-related lncRNAs signature with excellent clinical potency for an effective prognostic forecast of patients.

2021 ◽  
Vol 12 ◽  
Lu Meng ◽  
Jianfang Xu ◽  
Ying Ye ◽  
Yingying Wang ◽  
Shilan Luo ◽  

Radiotherapy is an effective local treatment modality of NSCLC. Its capabilities of eliminating tumor cells by inducing double strand DNA (dsDNA) damage and modulating anti-tumor immune response in irradiated and nonirradiated sites have been elucidated. The novel ICIs therapy has brought hope to patients resistant to traditional treatment methods, including radiotherapy. The integration of radiotherapy with immunotherapy has shown improved efficacy to control tumor progression and prolong survival in NSCLC. In this context, biomarkers that help choose the most effective treatment modality for individuals and avoid unnecessary toxicities caused by ineffective treatment are urgently needed. This article summarized the effects of radiation in the tumor immune microenvironment and the mechanisms involved. Outcomes of multiple clinical trials investigating immuno-radiotherapy were also discussed here. Furthermore, we outlined the emerging biomarkers for the efficacy of PD-1/PD-L1 blockades and radiation therapy and discussed their predictive value in NSCLC.

2021 ◽  
Vol 8 ◽  
Anaïs Boisson ◽  
Grégory Noël ◽  
Manuel Saiselet ◽  
Joël Rodrigues-Vitória ◽  
Noémie Thomas ◽  

Our expanding knowledge of the interactions between tumor cells and their microenvironment has helped to revolutionize cancer treatments, including the more recent development of immunotherapies. Immune cells are an important component of the tumor microenvironment that influence progression and treatment responses, particularly to the new immunotherapies. Technological advances that help to decipher the complexity and diversity of the tumor immune microenvironment (TIME) are increasingly used in translational research and biomarker studies. Current techniques that facilitate TIME evaluation include flow cytometry, multiplex bead-based immunoassays, chromogenic immunohistochemistry (IHC), fluorescent multiplex IHC, immunofluorescence, and spatial transcriptomics. This article offers an overview of our representative data, discusses the application of each approach to studies of the TIME, including their advantages and challenges, and reviews the potential clinical applications. Flow cytometry and chromogenic and fluorescent multiplex IHC were used to immune profile a HER2+ breast cancer, illustrating some points. Spatial transcriptomic analysis of a luminal B breast tumor demonstrated that important additional insight can be gained from this new technique. Finally, the development of a multiplex panel to identify proliferating B cells, Tfh, and Tfr cells on the same tissue section demonstrates their co-localization in tertiary lymphoid structures.

2021 ◽  
Vol 5 (1) ◽  
Siang-Boon Koh ◽  
Brian N. Dontchos ◽  
Veerle Bossuyt ◽  
Christine Edmonds ◽  
Simona Cristea ◽  

AbstractSystematic collection of fresh tissues for research at the time of diagnostic image-guided breast biopsy has the potential to fuel a wide variety of innovative studies. Here we report the initial experience, including safety, feasibility, and laboratory proof-of-principle, with the collection and analysis of research specimens obtained via breast core needle biopsy immediately following routine clinical biopsy at a single institution over a 14-month period. Patients underwent one or two additional core biopsies following collection of all necessary clinical specimens. In total, 395 patients were approached and 270 consented to the research study, yielding a 68.4% consent rate. Among consenting patients, 238 lesions were biopsied for research, resulting in 446 research specimens collected. No immediate complications were observed. Representative research core specimens showed high diagnostic concordance with clinical core biopsies. Flow cytometry demonstrated consistent recovery of hundreds to thousands of viable cells per research core. Among a group of HER2 + tumor research specimens, HER2 assessment by flow cytometry correlated highly with immunohistochemistry (IHC) staining, and in addition revealed extensive inter- and intra-tumoral variation in HER2 levels of potential clinical relevance. Suitability for single-cell transcriptomic analysis was demonstrated for a triple-negative tumor core biopsy, revealing substantial cellular diversity in the tumor immune microenvironment, including a prognostically relevant T cell subpopulation. Thus, collection of fresh tissues for research purposes at the time of diagnostic breast biopsy is safe, feasible and efficient, and may provide a high-yield mechanism to generate a rich tissue repository for a wide variety of cross-disciplinary research.

2021 ◽  
Paula Nieto ◽  
Marc Elosua-Bayes ◽  
Juan L. Trincado ◽  
Domenica Marchese ◽  
Ramon Massoni-Badosa ◽  

The tumor immune microenvironment is a main contributor to cancer progression and a promising therapeutic target for oncology. However, immune microenvironments vary profoundly between patients, and biomarkers for prognosis and treatment response lack precision. A comprehensive compendium of tumor immune cells is required to pinpoint predictive cellular states and their spatial localization. We generated a single-cell tumor immune atlas, jointly analyzing published data sets of >500,000 cells from 217 patients and 13 cancer types, providing the basis for a patient stratification based on immune cell compositions. Projecting immune cells from external tumors onto the atlas facilitated an automated cell annotation system. To enable in situ mapping of immune populations for digital pathology, we applied SPOTlight, combining single-cell and spatial transcriptomics data and identifying colocalization patterns of immune, stromal, and cancer cells in tumor sections. We expect the tumor immune cell atlas, together with our versatile toolbox for precision oncology, to advance currently applied stratification approaches for prognosis and immunotherapy.

2021 ◽  
Vol 12 ◽  
Xin Fan ◽  
YangShaobo Ou ◽  
Huijie Liu ◽  
Liangzhen Zhan ◽  
Xingrong Zhu ◽  

Background: Due to the lack of accurate guidance of biomarkers, the treatment of head and neck squamous cell carcinoma (HNSCC) has not been ideal. Ferroptosis plays an important role in tumor suppression and treatment of patients. However, tumor protein p53 (TP53) mutation may promote tumor progression through ferroptosis. Therefore, it is particularly important to mine prognostic-related differentially expressed ferroptosis-related genes (PR-DE-FRGs) in HNSCC to construct a prognostic model for accurately guiding clinical treatment.Methods: First, the HNSCC data obtained from The Cancer Genome Atlas (TCGA) was used to identify PR-DE-FRGs for screening candidate genes to construct a prognostic model. We not only used a variety of methods to verify the accuracy of the model for predicting prognosis but also explored the role of ferroptosis in the development of HNSCC from the perspective of the immune microenvironment and mutation. Finally, we explored the correlation between the prognostic model and clinical treatment and drew a high-precision nomogram to predict the prognosis.Results: Seventeen of the 29 PR-DE-FRGs were selected to construct a prognostic model with good predictive performance. Patients in the low-risk group were found to have a greater number of CD8 + T cells, follicular helper T cells, regulatory T cells, mast cells, T-cell costimulations, and type II interferon responses. A higher tumor mutation burden (TMB) was observed in the low-risk group and was associated with a better prognosis. A higher risk score was found in the TP53 mutation group and was associated with a worse prognosis. The risk score is closely related to the expression of immune checkpoint inhibitors (ICIs)-related genes such as PD-L1 and the IC50 of six chemotherapeutic drugs. The nomogram we constructed performs well in predicting prognosis.Conclusion: Ferroptosis may participate in the progression of HNSCC through the immune microenvironment and TP53 mutation. The model we built can be used as an effective predictor of immunotherapy and chemotherapy effects and prognosis of HNSCC patients.

2021 ◽  
zhenpeng zhu ◽  
Cuijian Zhang ◽  
Jinqin Qian ◽  
Ninghan Feng ◽  
Weijie Zhu ◽  

Abstract BackgroundRenal cell carcinoma is gradually characteristic of the accumulation of lipid-reactive oxygen species. And, the ferroptosis-related LncRNAs have been reported strongly correlated with tumorigenesis and progression. However, the further functions of ferroptosis-related LncRNAs in clear cell renal cell carcinoma have not been explored. MethodsAfter sample cleaning, data integration, and batch effect removal, we used the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) public database to screen out the expression and prognostic value of ferroptosis-related LncRNAs and then performed the molecular subtyping. The molecular subtyping was developed using the K-means. Then, the KEGG pathway enrichment and statistical analyses of the immune microenvironment and clusters were carried out. The outcomes indicated significant differences in the immune microenvironment and potential therapeutic targets between the two clusters. Then, LASSO Cox regression was performed to establish the 5-LncRNAs-based prognostic signature. The signature could accurately predict patient prognosis and be used as an independent clinical risk factor. And the 5 LncRNAs were validated in the cell lines and clinical samples. We then combined significant clinical parameters in multivariate Cox regression and prognostic signature to construct a clinical predictive nomogram, which provides appropriate guidance for predicting the overall survival of ccRCC patients.ResultsThe prognostic DEFRLncRNAs were identified, and 5 LncRNAs were finally utilized to establish the prognostic signature in the TCGA cohort, which was subsequently validated in the internal and external cohorts. Moreover, we conducted the molecular subtyping and divided the patients in the TCGA cohort into two clusters, showing the difference in the Hallmark pathways, immune infiltration, expression of the immune target, and drug therapy. Furthermore, the nomogram was established better to predict the clinical outcomes of the ccRCC patients. ConclusionsOur study conducted molecular subtyping and established a novel predictive signature based on the ferroptosis-related LncRNAs, which could accurately predict prognosis and potential therapeutic targets in ccRCC patients.

2021 ◽  
Congbo Yue ◽  
Tianyi Zhao ◽  
Shoucai Zhang ◽  
Yingjie Liu ◽  
Guixi Zheng ◽  

Abstract Alternative splicing (AS) events play a crucial role in the tumorigenesis and progression of cancer. Transcriptome data and Percent Spliced In (PSI) values of OV patients were downloaded from TCGA database and TCGA SpliceSeq. Totally we identified 1,472 AS events that were associated with survival of OV and exon skipping (ES) was the most important type. Univariate and multivariate Cox regression analysis were performed to identify survival-associated AS events and develop the prognostic model based on 11-AS events. The immune cells and different response to cytotoxic T lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) blockers in low-risk and high-risk group of OV patients were analyzed. Ten kinds of immune cells were found up-regulated in low-risk group. Activated B cell, natural killer T cell, natural killer cell and regulatory T cell were associated with survival of OV. The patients in low-risk group had good response to CTLA-4 and PD-1 blockers treatment. Moreover, a regulatory network was established according to the correlation between AS events and splicing factors (SFs). The present study provided valuable insights into the underlying mechanisms of OV. AS events that were correlated with the immune system might be potential therapeutic targets.

2021 ◽  
Xiangjin Hu ◽  
Sailun Wang ◽  
Jia Guo ◽  
Fang Xiong ◽  
Jun Lv

Abstract Background Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is the fourth leading cause of cancer-related death worldwide. Ferroptosis is a form of iron-dependent programmed cell death, and is characterized by intracellular accumulation of reactive oxygen species (ROS). Long non-coding RNAs (lncRNAs), as valuable prognostic factors for HCC patients, play a vital role in regulating ferroptosis. Methods RNA-sequencing datasets and ferroptosis-related genes were retrieved from The Cancer Genome Atlas (TCGA) database and the Molecular Signature Database. we performed Pearson correlation analysis between the lncRNAs and ferroptosis-related genes, and subsequently used regression analysis (univariate Cox analysis, multivariate Cox regression analysis, and Lasso regression analysis) to screen the ferroptosis-related lncRNAs with prognostic value in HCC, the prognostic ferroptosis-related lncRNAs signature (FRLS) was finally constructed. In addition, we reevaluated the model in terms of survival, clinical characteristics, and immune microenvironment. Results Univariate Cox regression analysis revealed 34 differently expressed ferroptosis-related lncRNAs related to the prognosis of HCC. Among them, 12 ferroptosis-related lncRNAs (LUCAT1, LINC01224, THUMPD3-AS1, AC116025.2, LINC00942, SNHG10, AC131009.1, POLH-AS1, MKLN1-AS, LINC01138, LNCSRLR, AL031985.3) were regarded as independent prognosis predictors of HCC, and were incorporated into the construction of the prognostic FRLS. Patients were divided into two groups based on the prognostic FRLS. Kaplan–Meier survival plot showed that patients in the high-risk groups exhibited shorter overall survival (OS) than those in low-risk groups (P < 0.001). Compared with clinical data, the area under curve (AUC) values of the risk factors, decision curve analysis (DCA), the AUC values of different years and multivariate Cox regression suggested that the signature had better predictive power. Gene set enrichment analysis (GSEA) revealed the potential pathways of 12 ferroptosis-related lncRNAs, including sphingolipid-metabolism, mTOR signaling pathway, notch signaling pathway, homologous recombination, endocytosis, cell cycle, etc. Immune microenvironment including tumor-infiltrating immune cells, immune-related functions, checkpoint-related genes and N6-methyladenosine (m6A)-related mRNA were also significantly different between the two risk groups. Conclusions This study constructed 12 FRLS for HCC patients to predict survival, which may provide promising targets for the therapy of HCC.

Liqin Ping ◽  
Kaiming Zhang ◽  
Xueqi Ou ◽  
Xingsheng Qiu ◽  
Xiangsheng Xiao

Background: Pyroptosis, a kind of programmed cell death characterized by the rupture of cell membranes and the release of inflammatory substances, plays an important role in the occurrence and development of cancer. However, few studies focus on the pyroptosis-associated long non-coding RNAs (lncRNAs) in breast cancer (BC). The prognostic value of pyroptosis-associated lncRNAs and their relationship with tumor microenvironment (TME) in BC remain unclear. The purpose of this study was to explore the prognostic role of pyroptosis-associated lncRNAs and their relationship with TME in BC.Methods: The transcriptome data and clinical data of female BC patients were downloaded from The Cancer Genome Atlas (TCGA) database. A total of 937 patients were randomly assigned to either training set or validation set. A pyroptosis-associated lncRNA signature was constructed in the training set and verified in the validation set. Functional analysis and immune microenvironment analysis related to pyroptosis-associated lncRNAs were performed. A nomogram based on the risk score and clinical characteristics was established.Results: A 9-pyroptosis-associated lncRNA signature was constructed to separate BC patients into two risk groups. High-risk patients had poorer prognosis than low-risk patients. The risk score was proven to be an independent prognostic factor by multivariate Cox regression analysis. Function analysis and immune microenvironment analysis showed that low-risk BC tended to be an immunologically “hot” tumor. A nomogram was constructed with risk score and clinical characteristics. Receiver operating characteristic curve (ROC) analysis demonstrated credible predictive power of the nomogram. The area under time-dependent ROC curve (AUC) reached 0.880 at 1 year, 0.804 at 3 years, and 0.769 at 5 years in the training set, and 0.799 at 1 year, 0.794 at 3 years, and 0.728 at 5 years in the validation set.Conclusion: We identified a novel pyroptosis-associated lncRNA signature that was an independent prognostic indicator for BC patients. Pyroptosis-associated lncRNAs had potential relationship with the immune microenvironment and might be therapeutic targets for BC patients.

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