Targeting Neuroinflammation in Brain Cancer: Uncovering Mechanisms, Pharmacological Targets, and Neuropharmaceutical Developments

Gliomas are one of the most lethal types of cancers accounting for ∼80% of all central nervous system (CNS) primary malignancies. Among gliomas, glioblastomas (GBM) are the most aggressive, characterized by a median patient survival of fewer than 15 months. Recent molecular characterization studies uncovered the genetic signatures and methylation status of gliomas and correlate these with clinical prognosis. The most relevant molecular characteristics for the new glioma classification are IDH mutation, chromosome 1p/19q deletion, histone mutations, and other genetic parameters such as ATRX loss, TP53, and TERT mutations, as well as DNA methylation levels. Similar to other solid tumors, glioma progression is impacted by the complex interactions between the tumor cells and immune cells within the tumor microenvironment. The immune system’s response to cancer can impact the glioma’s survival, proliferation, and invasiveness. Salient characteristics of gliomas include enhanced vascularization, stimulation of a hypoxic tumor microenvironment, increased oxidative stress, and an immune suppressive milieu. These processes promote the neuro-inflammatory tumor microenvironment which can lead to the loss of blood-brain barrier (BBB) integrity. The consequences of a compromised BBB are deleteriously exposing the brain to potentially harmful concentrations of substances from the peripheral circulation, adversely affecting neuronal signaling, and abnormal immune cell infiltration; all of which can lead to disruption of brain homeostasis. In this review, we first describe the unique features of inflammation in CNS tumors. We then discuss the mechanisms of tumor-initiating neuro-inflammatory microenvironment and its impact on tumor invasion and progression. Finally, we also discuss potential pharmacological interventions that can be used to target neuro-inflammation in gliomas.

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Analysis of Tumor Microenvironment Characteristics in Bladder Cancer: Implications for Immune Checkpoint Inhibitor Therapy

Frontiers in Immunology ◽

10.3389/fimmu.2021.672158 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xingyu Chen ◽

Haotian Chen ◽

Dong He ◽

Yaxin Cheng ◽

Yuxing Zhu ◽

...

Keyword(s):

Bladder Cancer ◽

Tumor Microenvironment ◽

Cancer Progression ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Immune Cell ◽

Cox Regression ◽

Prognostic Biomarker ◽

Checkpoint Inhibitor ◽

Clinical Prognosis

The tumor microenvironment (TME) plays a crucial role in cancer progression and recent evidence has clarified its clinical significance in predicting outcomes and efficacy. However, there are no studies on the systematic analysis of TME characteristics in bladder cancer. In this study, we comprehensively evaluated the TME invasion pattern of bladder cancer in 1,889 patients, defined three different TME phenotypes, and found that different subtypes were associated with the clinical prognosis and pathological characteristics of bladder cancer. We further explored the signaling pathways, cancer-immunity cycle, copy number, and somatic mutation differences among the different subtypes and used the principal component analysis algorithm to calculate the immune cell (IC) score, a tool for comprehensive evaluation of TME. Univariate and multivariate Cox regression analyses showed that ICscore is a reliable and independent prognostic biomarker. In addition, the use of anti-programmed death-ligand (PD-L1) treatment cohort, receiver operating characteristic (ROC) curve, Tumor Immune Dysfunction and Exclusion (TIDE), Subnetwork Mappings in Alignment of Pathways (SubMAP), and other algorithms confirmed that ICscore is a reliable prognostic biomarker for immune checkpoint inhibitor response. Patients with higher ICscore showed a significant therapeutic advantage in immunotherapy. In conclusion, this study improves our understanding of the characteristics of TME infiltration in bladder cancer and provides guidance for more effective personalized immunotherapy strategies.

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Molecular Characterization of the Clinical and Tumor Immune Microenvironment Signature of 5-methylcytosine-Related Regulators in non-small Cell Lung Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.779367 ◽

2021 ◽

Vol 9 ◽

Author(s):

Taisheng Liu ◽

Liyi Guo ◽

Guihong Liu ◽

Xiaoshan Hu ◽

Xiaoning Li ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Microenvironment ◽

Immune Cell ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Check Point ◽

Clinical Prognosis ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Immune Check Point Inhibitor

Background: DNA methylation is an important epigenetic modification, among which 5-methylcytosine methylation (5mC) is generally associated with tumorigenesis. Nonetheless, the potential roles of 5mC regulators in the tumor microenvironment (TME) remain unclear.Methods: The 5mC modification patterns of 1,374 lung adenocarcinoma samples were analyzed systematically. The correlation between the 5mC modification and tumor microenvironment cell infiltration was further assessed. The 5mCscore was developed to evaluate tumor mutation burden, immune check-point inhibitor response, and the clinical prognosis of individual tumors.Results: Three 5mC modification patterns were established based on the clinical characteristics of 21 5mC regulators. According to the differential expression of 5mC regulators, three distinct 5mC gene cluster were also identified, which showed distinct TME immune cell infiltration patterns and clinical prognoses. The 5mCscore was constructed to evaluate the tumor mutation burden, immune check-point inhibitor response, and prognosis characteristics. We found that patients with a low 5mCscore had significant immune cell infiltration and increased clinical benefit.Conclusion: This study indicated that the 5mC modification is involved in regulating TME infiltration remodeling. Targeting 5mC modification regulators might be a novel strategy to treat lung cancer.

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Immune Evasion Mechanism and AXL

Frontiers in Oncology ◽

10.3389/fonc.2021.756225 ◽

2021 ◽

Vol 11 ◽

Author(s):

Hye-Youn Son ◽

Hwan-Kyu Jeong

Keyword(s):

Tumor Microenvironment ◽

Immune Responses ◽

Signaling Pathway ◽

Immune Evasion ◽

Cell Activation ◽

Immune Cell ◽

Nk Cell ◽

Multiple Cancer ◽

Clinical Prognosis ◽

Programmed Death

Extensive interest in cancer immunotherapy is reported according to the clinical importance of CTLA-4 and (PD-1/PD-L1) [programmed death (PD) and programmed death-ligand (PD-L1)] in immune checkpoint therapies. AXL is a receptor tyrosine kinase expressed in different types of cancer and in relation to resistance against various anticancer therapeutics due to poor clinical prognosis. AXL and its ligand, i.e., growth arrest-specific 6 (GAS6) proteins, are expressed on many cancer cells, and the GAS6/AXL pathway is reported to promote cancer cell proliferation, survival, migration, invasion, angiogenesis, and immune evasion. AXL is an attractive and novel therapeutic target for impairing tumor progression from immune cell contracts in the tumor microenvironment. The GAS6/AXL pathway is also of interest immunologically because it targets fewer antitumor immune responses. In effect, several targeted therapies are selective and nonselective for AXL, which are in preclinical and clinical development in multiple cancer types. Therefore, this review focuses on the role of the GAS6/AXL signaling pathway in triggering the immunosuppressive tumor microenvironment as immune evasion. This includes regulating its composition and activating T-cell exclusion with the immune-suppressive activity of regulatory T cells, which is related to one of the hallmarks of cancer survival. Finally, this article discusses the GAS6/AXL signaling pathway in the context of several immune responses such as NK cell activation, apoptosis, and tumor-specific immunity, especially PD-1/PDL-1 signaling.

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Pan-cancer analysis identified inflamed microenvironment associated multi-omics signatures

10.1101/2020.03.17.996199 ◽

2020 ◽

Author(s):

Ben Wang ◽

Mengmeng Liu ◽

Zhujie Ran ◽

Xin Li ◽

Jie Li ◽

...

Keyword(s):

Tumor Microenvironment ◽

Single Cell ◽

Histone Deacetylase Inhibitors ◽

Immune Cell ◽

Cell Interaction ◽

Molecular Characteristics ◽

Molecular Features ◽

Phenotype Transformation ◽

Multiple Drugs ◽

Pan Cancer

AbstractBackgroundImmunotherapy has revolutionized cancer therapy. However, responses are not universal. The inflamed tumor microenvironment has been reported to correlate with response in tumor patients. However, how different tumors shape their tumor microenvironment remains a critical unsolved problem. A deeper insight into the molecular characteristics of inflamed tumor microenvironment may be needed.Materials and methodsHere, based on single-cell RNA sequencing technology and TCGA pan-cancer cohort, we investigated multi-omics molecular features of tumor microenvironment phenotypes. Based on single-cell RNA-seq analysis, we classified pan-cancer tumor samples into inflamed or non-inflamed tumor and identified molecular features of these tumors. Analysis of integrating identified gene signatures with a drug-genomic perturbation database identified multiple drugs which may be helpful for converting non-inflamed tumors to inflamed tumors.ResultsOur results revealed several inflamed/non-inflamed tumor microenvironments-specific molecular characteristics. For example, inflamed tumors highly expressed miR-650 and lncRNA including MIR155HG and LINC00426, these tumors showed activated cytokines-related signaling pathways. Interestingly, non-inflamed tumors tended to express several genes related to neurogenesis. Multi-omics analysis demonstrated the neuro phenotype transformation may be induced by hypomethylated promoters of these genes and down-regulated miR-650. Drug discovery analysis revealed histone deacetylase inhibitors may be a potential choice for helping favorable tumor microenvironment phenotype transformation and aiding current immunotherapy.ConclusionOur results provide a comprehensive molecular-level understanding of tumor cell-immune cell interaction and may have profound clinical implications.

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53 Unique insights into PDAC development revealed by both InSituPlex® and imaging mass cytometry

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.053 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A60-A60

Author(s):

Andrew Quong ◽

Mark Rees ◽

Kirsteen Maclean ◽

Mael Manesse ◽

Jordan Nieto ◽

...

Keyword(s):

Tumor Microenvironment ◽

Immune Cell ◽

Treatment Options ◽

Tumor Biology ◽

Membrane Integrity ◽

Ductal Adenocarcinoma ◽

Mass Cytometry ◽

Poor Overall Survival ◽

Immune Cell Population ◽

Clinical Prognosis

BackgroundPancreatic cancer remains a deadly disease due to difficulties hindering its early diagnosis, giving way to metastasis of the tumor and resulting in poor prognosis. While there are many neoplasms of the pancreas, pancreatic invasive ductal adenocarcinoma (PDAC) is the most common and treatment options are few, with poor overall survival. Aggressive surgeries such as the Whipple procedure coupled to systemic chemotherapy is one of the few treatment options. Recently, several publications have demonstrated improved outcomes with the inclusion of immunotherapy to cytotoxic drug combinations in some patients, however optimally selecting patients as candidates for immunotherapy-chemotherapy combinations remains a critical challenge. The complexities of the tumor microenvironment have been implicated in the failure of chemotherapy, radiation therapy, and immunotherapy. The tumor microenvironment of PDAC is especially rich with multiple interactions between pancreatic epithelial/cancer cells, stromal cells, immune cells and the extracellular matrix (ECM). PDACs are characterized by a complex ECM of desmoplastic reaction consisting of an extensive and dense fibrotic stroma that surrounds and infiltrates clusters of malignant epithelial cells, together with the loss of basement membrane integrity and an abnormal vasculature.MethodsIn the present study we demonstrate a tissue phenotyping workflow combining three complementary methods that can unravel novel insights in the complex tumor microenvironment. This novel translational workflow delivers tissue morphology information, spatial phenotyping of immune cell population on whole slides, and high dimensional imaging in selected regions of interest (ROI), by combining H&E, multiplex immunofluorescence (mIF), and Imaging Mass Cytometry (IMC™).ResultsThe use of the InSituPlex® UltiMapper® I/O PD-L1 kit enabled the streamlined combination and alignment of H&E and mIF data, leading to the strategic selection of relevant ROIs, while utility of IMC technology enabled downstream imaging of 35 protein markers associated with the ECM in the selected ROIs to provide a deeper understanding of the tumor microenvironment.ConclusionsThe incorporation of advanced multiplex imaging platforms such as mIF and IMC with routine H&E workflow in tumor biology can deliver some of the much-needed insight into tumor morphology, cellular composition, cellular functions, and cell-cell interactions and paves the way for potentially improved clinical prognosis and efficacy prediction in patients with cancer.

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Exploration of Redox-Related Molecular Patterns and the Redox Score for Prostate Cancer

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/4548594 ◽

2021 ◽

Vol 2021 ◽

pp. 1-28

Author(s):

Yue Wu ◽

Xi Zhang ◽

Huan Feng ◽

Bintao Hu ◽

Zhiyao Deng ◽

...

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Tumor Microenvironment ◽

Scoring System ◽

Drug Sensitivity ◽

Immune Cell ◽

Comprehensive Analysis ◽

The Cancer Genome Atlas ◽

Molecular Characteristics ◽

Driver Gene

Redox homeostasis is the key to cell survival, and its imbalance can promote the occurrence and progression of tumors. However, it remains unclear whether these redox-related genes (RRGs) have potential roles in the tumor microenvironment, immunotherapy, and drug sensitivity. Here, we performed a systematic and comprehensive analysis of 489 prostate cancer (PC) samples from The Cancer Genome Atlas database and 214 PC samples from 8 datasets in the Gene Expression Omnibus database to determine redox modification patterns and the redox scoring system for PC. We identified two modification patterns (Redox_A and Redox_B) in PC using unsupervised consensus clustering based on 1410 differential expression RRGs. We then compared the prognostic value, tumor microenvironment characteristics, immune cell infiltration, and molecular characteristics of the two patterns. The Redox_A pattern was significantly enriched in the carcinogenic activation signaling pathways and had a poor prognosis, while the Redox_B pattern was mainly enriched in a variety of metabolic and redox pathways and had a good prognosis. Next, redox-related characteristic genes were extracted from these two patterns, and a scoring system (Redox_score) was constructed to evaluate PC patients. Further analysis indicated that lower Redox_score patients had a better prognosis, while higher Redox_score patients had a higher tumor mutation burden, driver gene mutation rate, and immune checkpoint inhibitor gene expression. We also found that higher Redox_score patients were more responsive to anti-PD-1 immunotherapy. Moreover, Redox_score was determined to be significantly correlated with anticancer drug sensitivity and resistance. Our study provides a comprehensive analysis of redox modifications in PC and reveals new patterns of PC based on RRGs, which will provide insights into the complex mechanisms of PC and develop more effective individualized therapeutic strategies.

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Comprehensive Analysis of Pyroptosis-Related Genes and Tumor Microenvironment Infiltration Characterization in Breast Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2021.748221 ◽

2021 ◽

Vol 12 ◽

Author(s):

JianBin Wu ◽

Yuanyuan Zhu ◽

MingMin Luo ◽

Lei Li

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Immune Checkpoint ◽

Immune Cell ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Clinical Prognosis ◽

The Relationship ◽

Single Tumor

BackgroundImmunotherapy has emerged as a significant strategy to treat numerous tumors. The positive response to immunotherapy depends on the dynamic interaction between tumor cells and infiltrating lymphocytes in the tumor microenvironment (TME). Pyroptosis, inflammation-induced cell death, is intricately associated with several tumors. However, the relationship between pyroptosis and clinical prognosis, immune cell infiltration, and immunotherapy effect is unclear in breast cancer (BRCA).MethodsWe comprehensively evaluated 33 pyroptosis-related genes and systematically assessed the relationship between pyroptosis and tumor progression, prognosis, and immune cell infiltration. The PyroptosisScore was used to quantify the pyroptosis pattern of a single tumor patient. We then assessed their values for predicting prognoses and therapeutic responses in BRCA.ResultsThree different modes of PyroptosisClusters were determined. The characteristics of TME cell infiltration in these three PyroptosisClusters were highly consistent with three immunophenotypes of tumors, including immune-excluded, immune-inflamed, and immune-desert phenotypes. Comprehensive bioinformatics analysis revealed that patients with a low PyroptosisScore had higher immune checkpoint expression, higher immune checkpoint inhibitor (ICI) scores, increased immune microenvironment infiltration, and were more sensitive to immunotherapy than those with a high PyroptosisScore.ConclusionsOur findings revealed the crucial role of pyroptosis in maintaining the diversity and complexity of TME. Pyroptosis is closely related to tumor progression, tumor prognosis, and immunotherapy response. Evaluating the PyroptosisScore of a single tumor can assist in understanding the characteristics of TME infiltration and lead to the development of more effective immunotherapy strategies.

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Gas6/Axl Signaling Pathway in the Tumor Immune Microenvironment

Cancers ◽

10.3390/cancers12071850 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1850 ◽

Cited By ~ 1

Author(s):

Mai Tanaka ◽

Dietmar W. Siemann

Keyword(s):

Tumor Microenvironment ◽

Signaling Pathway ◽

Immune Evasion ◽

Tyrosine Kinases ◽

Immune Cell ◽

Expression Patterns ◽

Therapy Resistance ◽

Host Cells ◽

Clinical Prognosis

Receptor tyrosine kinases have been shown to dysregulate a number of pathways associated with tumor development, progression, and metastasis. Axl is a receptor tyrosine kinase expressed in many cancer types and has been associated with therapy resistance and poor clinical prognosis and outcomes. In addition, Axl and its ligand growth arrest specific 6 (Gas6) protein are expressed by a number of host cells. The Gas6/Axl signaling pathway has been implicated in the promotion of tumor cell proliferation, survival, migration, invasion, angiogenesis, and immune evasion. As a result, Axl is an attractive, novel therapeutic target to impair multiple stages of tumor progression from both neoplastic and host cell axes. This review focuses on the role of the Gas6/Axl signaling pathway in promoting the immunosuppressive tumor microenvironment, as immune evasion is considered one of the hallmarks of cancer. The review discusses the structure and activation of the Gas6/Axl signaling pathway, GAS6 and AXL expression patterns in the tumor microenvironment, mechanisms of Axl-mediated tumor immune response, and the role of Gas6/Axl signaling in immune cell recruitment.

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

Cancer Letters ◽

10.1016/j.canlet.2021.02.013 ◽

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

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Recent Advancements on Immunomodulatory Mechanisms of Resveratrol in Tumor Microenvironment

Molecules ◽

10.3390/molecules26051343 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1343

Author(s):

Gagan Chhabra ◽

Chandra K. Singh ◽

Deeba Amiri ◽

Neha Akula ◽

Nihal Ahmad

Keyword(s):

Tumor Microenvironment ◽

Immune Cell ◽

Cancer Therapies ◽

Regulatory Cells ◽

Immunomodulatory Effects ◽

Cancer Management ◽

Natural Agents ◽

Anticancer Effects ◽

Cancer Types ◽

Immune Related Genes

Immunomodulation of the tumor microenvironment is emerging as an important area of research for the treatment of cancer patients. Several synthetic and natural agents are being investigated for their ability to enhance the immunogenic responses of immune cells present in the tumor microenvironment to impede tumor cell growth and dissemination. Among them, resveratrol, a stilbenoid found in red grapes and many other natural sources, has been studied extensively. Importantly, resveratrol has been shown to possess activity against various human diseases, including cancer. Mechanistically, resveratrol has been shown to regulate an array of signaling pathways and processes involving oxidative stress, inflammation, apoptosis, and several anticancer effects. Furthermore, recent research suggests that resveratrol can regulate various cellular signaling events including immune cell regulation, cytokines/chemokines secretion, and the expression of several other immune-related genes. In this review, we have summarized recent findings on resveratrol’s effects on immune regulatory cells and associated signaling in various cancer types. Numerous immunomodulatory effects of resveratrol suggest it may be useful in combination with other cancer therapies including immunotherapy for effective cancer management.

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