scholarly journals Multi-Omics Analysis of Novel Signature for Immunotherapy Response and Tumor Microenvironment Regulation Patterns in Urothelial Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Guangdi Chu ◽  
Wenhong Shan ◽  
Xiaoyu Ji ◽  
Yonghua Wang ◽  
Haitao Niu
Keyword(s):  
Tumor Microenvironment ◽  
Urothelial Cancer ◽  
Therapeutic Response ◽  
Penalized Regression ◽  
Molecular Characteristics ◽  
M1 Macrophage ◽  
The Status ◽  
Precision Therapy ◽  
Stromal Activation ◽  
Patient Prognosis

The tumor microenvironment (TME) is mainly composed of tumor cells, tumor-infiltrating immune cells, and stromal components. It plays an essential role in the prognosis and therapeutic response of patients. Nonetheless, the TME landscape of urothelial cancer (UC) has not been fully elucidated. In this study, we systematically analyzed several UC cohorts, and three types of TME patterns (stromal-activation subtype, immune-enriched subtype and immune-suppressive subtype) were defined. The tumor microenvironment signature (TMSig) was constructed by modified Lasso penalized regression. Patients were stratified into high- and low-TMSig score groups. The low-score group had a better prognosis (p < 0.0001), higher M1 macrophage infiltration (p < 0.01), better response to immunotherapy (p < 0.05), and more similar molecular characteristics to the luminal (differentiated) subtype. The accuracy of the TMSig for predicting the immunotherapy response was also verified in three independent cohorts. We highlighted that the TMSig is an effective predictor of patient prognosis and immunotherapy response. Quantitative evaluation of a single sample is valuable for us to combine histopathological and molecular characteristics to comprehensively evaluate the status of the patient. Targeted macrophage treatment has great potential for the individualized precision therapy of UC patients.

scholarly journals Identification of an immune gene expression signature associated with favorable clinical features in Treg-enriched patient tumor samples

2018 ◽  
Author(s):  
Kevin B. Givechian ◽  
Kamil Wnuk ◽  
Chad Garner ◽  
Stephen Benz ◽  
Hermes Garban ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Adaptive Immune Response ◽  
Gene Expression Signature ◽  
Gene Signature ◽  
Clinical Feature ◽  
Immune Gene ◽  
M1 Macrophage ◽  
Patient Prognosis

AbstractImmune heterogeneity within the tumor microenvironment undoubtedly adds several layers of complexity to our understanding of drug sensitivity and patient prognosis across various cancer types. Within the tumor microenvironment, immunogenicity is a favorable clinical feature in part driven by the antitumor activity of CD8+ T cells. However, tumors often inhibit this antitumor activity by exploiting the suppressive function of Regulatory T cells (Tregs), thus suppressing the adaptive immune response. Despite the seemingly intuitive immunosuppressive biology of Tregs, prognostic studies have produced contradictory results regarding the relationship between Treg enrichment and survival. We therefore analyzed RNA-seq data of Treg-enriched tumor samples to derive a pan-cancer gene signature able to help reconcile the inconsistent results of Treg studies, by better understanding the variable clinical association of Tregs across alternative tumor contexts. We show that increased expression of a 32-gene signature in Treg-enriched tumor samples (n=135) is able to distinguish a cohort of patients associated with chemosensitivity and overall survival This cohort is also enriched for CD8+ T cell abundance, as well as the antitumor M1 macrophage subtype. With a subsequent validation in a larger TCGA pool of Treg-enriched patients (n = 626), our results reveal a gene signature able to produce unsupervised clusters of Treg-enriched patients, with one cluster of patients uniquely representative of an immunogenic tumor microenvironment. Ultimately, these results support the proposed gene signature as a putative biomarker to identify certain Treg-enriched patients with immunogenic tumors that are more likely to be associated with features of favorable clinical outcome.

The tumor microenvironment shapes the molecular characteristics of exhausted CD8+ T cells

2021 ◽  
Vol 506 ◽  
pp. 55-66
Author(s):  
Hongcheng Cheng ◽  
Kaili Ma ◽  
Lianjun Zhang ◽  
Guideng Li
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Molecular Characteristics

scholarly journals EXTH-65. USING METHYLATION PROFILES TO GUIDE THE REPURPOSING OF CHEMOTHERAPIES AGAINST HIGH-RISK MENINGIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii101-ii101
Author(s):  
Anh Tran ◽  
Denise Scholtens ◽  
Lyndsee Zhang ◽  
Jenny Pokorny ◽  
Aneta Baran ◽  
...  
Keyword(s):  
Apoptotic Cell ◽  
Progression Free Survival ◽  
Brain Structures ◽  
Primary Brain Tumor ◽  
Molecular Characteristics ◽  
Cpg Sites ◽  
Hazard Ratios ◽  
The Us ◽  
Patient Prognosis ◽  
Raloxifene Hydrochloride

Abstract Meningioma is the most common primary brain tumor with nearly thirty thousand new cases in the US every year. While most meningiomas grow slowly, hence categorized as benign, they can still impact brain structures and result in disability or lethality. Currently, there is no widely accepted chemotherapy for meningioma, and our understanding of the disease’s molecular characteristics is very limited. In this study, we aimed to identify druggable molecular targets for repurposing of chemotherapies against meningiomas. We analyzed previously published dataset of 493 meningioma patients by Felix Sahm et al (Lancet Oncology, 2017) for association with progression-free survival (PFS) and identified associations of methylation at individual CpG sites as detected by the Illumina 450k platform with PFS. Subsequently, we searched for candidate drugs targeting the pathways linked to poor patient prognosis. Our analyses indicated 981 genes for which methylation of mapped CpG sites was found to be consistently associated with shorter PFS (positive hazard ratios (HRs)) and with longer PFS (negative HRs) at FDR-adjusted p < 0.05. Using Cytoscape/Reactome FI app, we cross-referenced current cancer drugs that target these and identified docetaxel and raloxifene hydrochloride as potential candidates. In our vitro study, docetaxel caused apoptotic cell death in established and primary patient meningioma lines of various grades. IC50s of docetaxel in the sixteen meningioma cell lines tested ranged from 0.8nM to 4.4mM, which partially corresponded to the growth rates of these cells. Our study will advance our understanding of molecular pathways driving meningioma and identify potential targeted therapies to bridge the current gap in treatment of the disease.

Molecular subtypes of upper tract urothelial cancer: Setting the stage for precision therapy

Cancer Cell ◽  
2021 ◽  
Vol 39 (6) ◽  
pp. 745-747
Author(s):  
David J. McConkey ◽  
Nirmish Singla ◽  
Phillip Pierorazio ◽  
Kara Lombardo ◽  
Andres Matoso ◽  
...  
Keyword(s):  
Urothelial Cancer ◽  
Molecular Subtypes ◽  
Upper Tract ◽  
Precision Therapy ◽  
Upper Tract Urothelial Cancer ◽  
Cancer Setting

scholarly journals Identification of a 5-Gene Metabolic Signature for Predicting Prognosis Based on an Integrated Analysis of Tumor Microenvironment in Lung Adenocarcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Xiaolin Yu ◽  
Xiaomei Zhang ◽  
Yanxia Zhang
Keyword(s):  
Tumor Microenvironment ◽  
Confidence Interval ◽  
Lung Adenocarcinoma ◽  
Cox Regression ◽  
External Validation ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Integrated Analysis ◽  
Lasso Regression ◽  
The Status

Lung adenocarcinoma (LUAD) is a common subtype of lung cancer with a depressing survival rate. The reprogramming of tumor metabolism was identified as a new hallmark of cancer in tumor microenvironment (TME), and we made a comprehensive exploration to reveal the prognostic role of the metabolic-related genes. Transcriptome profiling data of LUAD were, respectively, downloaded from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. Based on the extracted metabolic-related genes, a novel 5-gene metabolic prognostic signature (including GNPNAT1, LPGAT1, TYMS, LDHA, and PTGES) was constructed by univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression. This signature confirmed its robustness and accuracy by external validation in multiple databases. It could be an independent risk factor for LUAD, and the nomograms possessed moderately accurate performance with the C-index of 0.755 (95% confidence interval: 0.706–0.804) and 0.691 (95% confidence interval: 0.636–0.746) in training set and testing set. This signature could reveal the metabolic features according to the results of gene set enrichment analysis (GSEA) and meanwhile monitor the status of TME through ESTIMATE scores and the infiltration levels of immune cells. In conclusion, this gene signature is a cost-effective tool which could indicate the status of TME to provide more clues in the exploration of new diagnostic and therapeutic strategy.

Differential Diagnosis and Precision Therapy of Two Typical Malignant Cutaneous Tumors Leveraging Their Tumor Microenvironment: A Photomedicine Strategy

ACS Nano ◽  
2019 ◽  
Vol 13 (10) ◽  
pp. 11168-11180 ◽  
Author(s):  
Peiru Wang ◽  
Weitao Yang ◽  
Shuzhan Shen ◽  
Chao Wu ◽  
Long Wen ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Tumor Microenvironment ◽  
Precision Therapy

scholarly journals Positron Emission Tomography for Response Evaluation in Microenvironment-Targeted Anti-Cancer Therapy

Biomedicines ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 371
Author(s):  
Noboru Oriuchi ◽  
Shigeyasu Sugawara ◽  
Tohru Shiga
Keyword(s):  
Positron Emission Tomography ◽  
Tumor Microenvironment ◽  
Cancer Therapy ◽  
Fdg Pet ◽  
Cell Tracking ◽  
Therapeutic Response ◽  
Tumor Response ◽  
Checkpoint Inhibitors ◽  
Emission Tomography ◽  
Positron Emission

Therapeutic response is evaluated using the diameter of tumors and quantitative parameters of 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET). Tumor response to molecular-targeted drugs and immune checkpoint inhibitors is different from conventional chemotherapy in terms of temporal metabolic alteration and morphological change after the therapy. Cancer stem cells, immunologically competent cells, and metabolism of cancer are considered targets of novel therapy. Accumulation of FDG reflects the glucose metabolism of cancer cells as well as immune cells in the tumor microenvironment, which differs among patients according to the individual immune function; however, FDG-PET could evaluate the viability of the tumor as a whole. On the other hand, specific imaging and cell tracking of cancer cell or immunological cell subsets does not elucidate tumor response in a complexed interaction in the tumor microenvironment. Considering tumor heterogeneity and individual variation in therapeutic response, a radiomics approach with quantitative features of multimodal images and deep learning algorithm with reference to pathologic and genetic data has the potential to improve response assessment for emerging cancer therapy.

scholarly journals From Genetic Alterations to Tumor Microenvironment: The Ariadne’s String in Pancreatic Cancer

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 309 ◽  
Author(s):  
Chiara Bazzichetto ◽  
Fabiana Conciatori ◽  
Claudio Luchini ◽  
Francesca Simionato ◽  
Raffaela Santoro ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Myeloid Cells ◽  
Genetic Alterations ◽  
Molecular Characteristics ◽  
Precision Oncology ◽  
Cancer Type ◽  
Tumor Type ◽  
Driver Genes

The threatening notoriety of pancreatic cancer mainly arises from its negligible early diagnosis, highly aggressive progression, failure of conventional therapeutic options and consequent very poor prognosis. The most important driver genes of pancreatic cancer are the oncogene KRAS and the tumor suppressors TP53, CDKN2A, and SMAD4. Although the presence of few drivers, several signaling pathways are involved in the oncogenesis of this cancer type, some of them with promising targets for precision oncology. Pancreatic cancer is recognized as one of immunosuppressive phenotype cancer: it is characterized by a fibrotic-desmoplastic stroma, in which there is an intensive cross-talk between several cellular (e.g., fibroblasts, myeloid cells, lymphocytes, endothelial, and myeloid cells) and acellular (collagen, fibronectin, and soluble factors) components. In this review; we aim to describe the current knowledge of the genetic/biological landscape of pancreatic cancer and the composition of its tumor microenvironment; in order to better direct in the intrinsic labyrinth of this complex tumor type. Indeed; disentangling the genetic and molecular characteristics of cancer cells and the environment in which they evolve may represent the crucial step towards more effective therapeutic strategies

Impact of chemoradiotherapy (CRT) on immune-related tumor microenvironment and the efficacy of anti-PD-1 therapy after the recurrence of CRT in unresectable locally advanced NSCLC patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21719-e21719
Author(s):  
Masayuki Shirasawa ◽  
Tatsuya Yoshida ◽  
Noriko Motoi ◽  
Yuji Matsumoto ◽  
Yuki Shinno ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Advanced Nsclc ◽  
Locally Advanced ◽  
Antibody Therapy ◽  
Progression Free Survival ◽  
Expression Levels ◽  
Locally Advanced Nsclc ◽  
The Status ◽  
History Of ◽  
Nsclc Patients

e21719 Background: Chemoradiotherapy (CRT) followed by durvalumab as maintenance therapy prolonged progression-free survival (PFS) and overall survival (OS) in unresectable locally advanced NSCLC (LA-NSCLC). Additionally, the history of radiotherapy and CRT has been reported to increase the efficacy of PD-1 blockade in advanced NSCLC patients. We evaluated the efficacy of anti-PD-(L)1 antibody therapy after CRT failure, and how CRT changes the status of PD-L1 expression on tumors and tumor infiltrated lymphocytes (TILs) in tumor microenvironment (TME) in unresectable LA-NSCLC patients. Methods: We retrospectively reviewed unresectable LA-NSCLC patients treated with CRT between December 2007 and December 2018, and evaluated the efficacy of PD-1 blockade after CRT failure. We also analyzed PD-L1 (clone: 22C3) expression on tumor cells, and CD8 positive TILs using the paired specimens that had been obtained pre-CRT and post-CRT failure. Results: We identified 422 patients who received CRT. Median follow-up was 36.1 months (range 2.7–138.1 months). Among these patients, sixty-five patients who had progressed post-CRT received anti-PD- (L)1 therapy (PD-1 therapy: 61 patients, PD-L1 therapy: 4 patients). Response rate (RR) and PFS of anti-PD-(L)1 therapy were 48% (95% CI, 35–60) and 8.7 (95% CI, 4.5–13.0) months. The RR and PFS did not differ according to PD-L1 expression levels (Table). Of the 18 patients, 9, 7, and 2 showed upregulation in PD-L1 expression or down- or no change, respectively, post-CRT. In contrast, the density of CD8 positive TILs in TME increased by CRT treatment ([pre-CRT]: median, 110 ± 239 /mm2 vs. [post-CRT]: median, 470 ± 533 /mm2, p = 0.025). Conclusions: The clinical outcome of anti-PD-(L)1 therapy after CRT failure in LA-NSCLC patients could be better than advanced NSCLC patients, but did not differ according to PD-L1 expression levels. The efficacy of PD-(L)1 therapy enhanced by CRT treatment could be due to the infiltration of CD8 T-cells into TME. [Table: see text]

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