Tumor Microenvironment Research Articles

Research on the Regulatory Mechanism of Ginseng on the Tumor Microenvironment of Colorectal Cancer based on Network Pharmacology and Bioinformatics Validation.

A network pharmacology study on the biological action of ginseng in the treatment of colorectal cancer (CRC) by regulating the tumor microenvironment (TME). To investigate the potential mechanism of action of ginseng in the treatment of CRC by regulating TME. This research employed network pharmacology, molecular docking techniques, and bioinformatics validation. Firstly, the active ingredients and the corresponding targets of ginseng were retrieved using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), the Traditional Chinese Medicine Integrated Database (TCMID), and the Traditional Chinese Medicine Database@Taiwan (TCM Database@Taiwan). Secondly, the targets related to CRC were retrieved using Genecards, Therapeutic Target Database (TTD), and Online Mendelian Inheritance in Man (OMIM). Tertiary, the targets related to TME were derived from screening the GeneCards and National Center for Biotechnology Information (NCBI)-Gene. Then the common targets of ginseng, CRC, and TME were obtained by Venn diagram. Afterward, the Protein-protein interaction (PPI) network was constructed in the STRING 11.5 database, intersecting targets identified by PPI analysis were introduced into Cytoscape 3.8.2 software cytoHubba plugin, and the final determination of core targets was based on degree value. The OmicShare Tools platform was used to analyze the Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the core targets. Autodock and PyMOL were used for molecular docking verification and visual data analysis of docking results. Finally, we verified the core targets by Gene Expression Profiling Interactive Analysis (GEPIA) and Human Protein Atlas (HPA) databases in bioinformatics. A total of 22 active ingredients and 202 targets were identified to be closely related to the TME of CRC. PPI network mapping identified SRC, STAT3, PIK3R1, HSP90AA1, and AKT1 as possible core targets. Go enrichment analysis showed that it was mainly involved in T cell co-stimulation, lymphocyte co-stimulation, growth hormone response, protein input, and other biological processes; KEGG pathway analysis found 123 related signal pathways, including EGFR tyrosine kinase inhibitor resistance, chemokine signaling pathway, VEGF signaling pathway, ErbB signaling pathway, PD-L1 expression and PD-1 checkpoint pathway in cancer, etc. The molecular docking results showed that the main chemical components of ginseng have a stable binding activity to the core targets. The results of the GEPIA database showed that the mRNA levels of PIK3R1 were significantly lowly expressed and HSP90AA1 was significantly highly expressed in CRC tissues. Analysis of the relationship between core target mRNA levels and the pathological stage of CRC showed that the levels of SRC changed significantly with the pathological stage. The HPA database results showed that the expression levels of SRC were increased in CRC tissues, while the expression of STAT3, PIK3R1, HSP90AA1, and AKT1 were decreased in CRC tissues. Ginseng may act on SRC, STAT3, PIK3R1, HSP90AA1, and AKT1 to regulate T cell costimulation, lymphocyte costimulation, growth hormone response, protein input as a molecular mechanism regulating TME for CRC. It reflects the multi-target and multi-pathway role of ginseng in modulating TME for CRC, which provides new ideas to further reveal its pharmacological basis, mechanism of action and new drug design and development.

Integrated immuno-transcriptomic analysis of ovarian cancer identifies a four-chemokine-dominated subtype with antitumor immune-active phenotype and favorable prognosis.

Ovarian cancer (OV) is a heterogeneous disease but has traditionally been treated as an immunologically cold malignancy. The relationship between the immune-active cancer phenotype typified by a T helper 1 (Th-1) immune response and clinical outcome in OV remains uncertain. A cohort-scale compendium of transcriptomic data from 2850 OV samples from 19 individual datasets was compiled for integrative immuno-transcriptomic analysis. The immunological constant of rejection was used as a metric to assess the Th-1/cytotoxic response orientation and investigate the clinical-biological significance of immune polarization towards a Th-1 immune response. Single-cell RNA sequencing data from 39 OV samples were analyzed to elucidate the variability of the immune microenvironment, and immunohistochemical validation was performed on 39 samples from the Harbin Medical University Cancer Hospital. Our results demonstrated the prognostic significance of a Th-1/cytotoxic immune profile within the tumor microenvironment (TME) using the immunological constant of rejection classification to OV samples. Specifically, patients with tumors expressing high levels of ICR markers showed significantly improved survival. A gene panel consisting of four chemokines (CXCL9, CXCL10, CXCL11 and CXCL13) was identified as critical players in mediating the establishment of an active T-cell-inflamed antitumor phenotype. This 4-chemokine signature, which was extensively validated in external multicenter cohorts through transcriptomic profiling and in an independent in-house cohort through immunohistochemistry, introduced a novel immune classification in OV and identified a chemokine-dominated subtype associated with an active antitumor immune phenotype and favorable prognosis. Single-cell transcriptomic analysis revealed that chemokine-dominated tumors increase CXCR3 + NK and T cell recruitment to the TME primarily through the overexpression of macrophage-derived CXCL9/10/11. This study provides new insights into understanding immune heterogeneity within the TME and paves the way for tailoring appropriate therapeutic interventions for patients with differing immune profiles.

Rapid Autopsy to Define Dendritic Cell Spatial Distribution and T Cell Association in Lung Adenocarcinoma.

Immunotherapy response is associated with the presence of conventional dendritic cells (cDCs). cDC type 1 (cDC1) is critically important for CD8+ T cell activation, cDC type 2 (cDC2) regulates CD4+ T cell responses, and mature regulatory cDCs may dampen T cell responses in the tumor microenvironment (TME). However, we lack a clear understanding of cDC distribution in the human TME, cDC prevalence in metastatic sites, and cDC differences in early- versus late-stage disease. Rapid autopsy specimens of 10 patients with lung adenocarcinoma were evaluated to detect cDCs and immune cells via multiplex immunofluorescence using 18 markers and 42 tumors. First, we found that T cells, cDC1, and cDC2 were confined to stroma, whereas mature regulatory DCs were enriched in tumor, suggesting unique localization-specific functions. Second, lung and lymph node tumors were more enriched in T cells and cDCs than liver tumors, underscoring differences in the TME of metastatic sites. Third, although the proportion of T cells and cDC1 did not differ in different stages, an increase in the proportion of cDC2 and macrophages in late stage suggests potential differences in regulation of T cell responses in different stages. Collectively, these findings provide new, to our knowledge, insights into cDC biology in human cancer that may have important therapeutic implications.

Identification of Necroptosis-related Molecular Subtypes and Construction of Necroptosis-related Gene Signature for Glioblastoma Multiforme.

Necroptosis is a highly regulated and genetically controlled process, and therefore, attention has been paid to the exact effects of this disorder on a variety of diseases, including cancer. An in-depth understanding of the key regulatory factors and molecular events that trigger necroptosis can not only identify patients at risk of cancer development but can also help to develop new treatment strategies. This study aimed to increase understanding of the complex role of necroptosis in glioblastoma multiforme (GBM) and provide a new perspective and reference for accurate prediction of clinical outcomes and gene-targeted therapy in patients with GBM. The objective of this study was to analyze the gene expression profile of necroptosis regulatory factors in glioblastoma multiforme (GBM) and establish a necroptosis regulatory factor-based GBM classification and prognostic gene signature to recognize the multifaceted impact of necroptosis on GBM. The necroptosis score of the glioblastoma multiforme (GBM) sample in TCGA was calculated by ssGSEA, and the correlation between each gene and the necroptosis score was calculated. Based on necroptosis score-related genes, unsupervised consensus clustering was employed to classify patients. The prognosis, tumor microenvironment (TME), genomic changes, biological signal pathways and gene expression differences among clusters were analyzed. The gene signature of GBM was constructed by Cox and LASSO regression analysis of differentially expressed genes (DEGs). Based on 34 necroptosis score-related genes, GBM was divided into two clusters with different overall survival (OS) and TME. A necroptosis-related gene signature (NRGS) containing 8 genes was developed, which could stratify the risk of GBM in both the training set and verification set and had good prognostic value. NRGS and age were both independent prognostic indicators of GBM, and a nomogram developed by the integration of both of them showed a better predictive effect than traditional clinical features. In this study, patients from public data sets were divided into two clusters and the unique TME and molecular characteristics of each cluster were described. Furthermore, an NRGS was constructed to effectively and independently predict the survival outcome of GBM, which provides some insights for the implementation of personalized precision medicine in clinical practice.

Modulatory Role of Phytochemicals/Natural Products in Cancer Immunotherapy.

Immunotherapy is a newly emerging and effective approach to treating cancer. However, there are many challenges associated with using checkpoint inhibitors in this treatment strategy. The component of the tumor microenvironment plays a crucial role in antitumor immune response, regulating tumor immune surveillance and immunological evasion. Natural products/phytochemicals can modulate the tumor microenvironment and function as immunomodulatory agents. In clinical settings, there is a strong need to develop synergistic combination regimens using natural products that can effectively enhance the therapeutic benefits of immune checkpoint inhibitors relative to their effectiveness as single therapies. The review discusses immunotherapy, its side effects, and a summary of evidence suggesting the use of natural products to modulate immune checkpoint pathways.

The immune microenvironment of cancer of the uterine cervix.

While several treatment choices exist for cervical cancer, such as surgical therapy, chemotherapy, and radiotherapy, some patients will still show poor prognosis. HPV infection is a principal factor for cervical cancer development, from early inflammation to proliferation, angiogenesis, and neoplastic growth. While HPV T-cell responses exist, the tumor seems to evade the immune system upon its tolerance. The latter suggests the existence of a confluent tumor microenvironment responsible for the evasion tactics employed by the neoplasm. Therefore, novel biomarkers governing prognosis and treatment planning must be developed, with several studies tackling the significance of the tumor microenvironment in the genesis, development, proliferation, and overall response of cervical cancer during neoplastic processes. This review aims to analyze and contemplate the characteristics of the tumor microenvironment and its role in prognosis, progression, evasion, and invasion, including therapeutic outcome and overall survival.

Association of Collagen Changes in Distal Anastomotic Margin and Anastomotic Stenosis after Neoadjuvant Chemoradiotherapy for Rectal Cancer.

Neoadjuvant chemoradiotherapy (nCRT) for rectal cancer can lead to structural changes in collagen in the tumor microenvironment and increase the risk of postoperative anastomotic stenosis (AS). However, the quantitative relationship between AS and collagen has not been defined. This study is to quantitatively analyze the collagen features in rectal cancer and explore the relationship between the changes of collagen and postoperative anastomotic stenosis after nCRT. This is a retrospective study. A total of 371 patients with rectal cancer were included. Collagen features in the resection margin of rectal cancer anastomosis was extracted by multiphoton imaging. The least absolute shrinkage operator logistic regression was performed to select features related to AS and the collagen score (CS) was constructed. Area under the receiver operating curve (AUROC) and decision curve analysis were performed to evaluate the discrimination and clinical benefit of the nomogram. The probability of AS was 23% in the training cohort and 15.9% in the validation cohort. In the training cohort, the distance between tumor and resection margin, anastomotic leakage and CS were independent risk factors for postoperative AS in univariate and multivariate analyses. A nomogram was constructed based on these results. The prediction nomogram showed good discrimination (AUROC 0.864; 95% CI 0.776 to 0.952) and was validated in the validation cohort (AUROC 0.918; 95% CI 0.851 to 0.985). CS is an independent risk factor for AS in rectal cancer after nCRT. The predictive model based on CS can predict the occurrence of postoperative AS.

Inhibition of the Rho/MRTF pathway improves the response of BRAF-resistant melanoma to PD1/PDL1 blockade.

Metastatic cutaneous melanoma is a fatal skin cancer. Resistance to targeted and immune therapies limits the benefits of current treatments. Identifying and adding anti-resistance agents to current treatment protocols can potentially improve clinical responses. Myocardin-related transcription factor (MRTF) is a transcriptional coactivator whose activity is indirectly regulated by actin and the Rho family of GTPases. We previously demonstrated that development of BRAF inhibitor (BRAFi) resistance frequently activates the Rho/MRTF pathway in human and mouse BRAFV600E melanomas. In clinical trials, pretreatment with BRAFi reduces the benefit of immune therapies. We aimed to test the efficacy of concurrent treatment with our MRTF pathway inhibitor CCG-257081 and anti-PD1 in vivo and to examine its effects on the melanoma immune microenvironment. Because MRTF pathway activation upregulates the expression of immune checkpoint inhibitor genes/proteins, we asked whether CCG-257081 can improve the response to immune checkpoint blockade. CCG-257081 reduced the expression of PDL1 in BRAFi-resistant melanoma cells and decreased surface PDL1 levels on both BRAFi-sensitive and -resistant melanoma cells. Using our recently described murine vemurafenib-resistant melanoma model, we found that CCG-257081, in combination with anti-PD1 immune therapy, reduced tumor growth and increased survival. Moreover, anti-PD1/CCG-257081 co-treatment increased infiltration of CD8+ T cells and B cells into the tumor microenvironment and reduced tumor-associated macrophages. Here, we propose CCG-257081 as an anti-resistance and immune therapy-enhancing anti-melanoma agent.

RNAs in tumour-derived extracellular vesicles and their significance in the tumour microenvironment.

Small extracellular vesicles (sEVs) secreted by various types of cells serve as crucial mediators of intercellular communication within the complex tumour microenvironment (TME). Tumour-derived small extracellular vesicles (TDEs) are massively produced and released by tumour cells, recapitulating the specificity of their cell of origin. TDEs encapsulate a variety of RNA species, especially messenger RNAs, microRNAs, long non-coding RNAs, and circular RNAs, which release to the TME plays multifaced roles in cancer progression through mediating cell proliferation, invasion, angiogenesis, and immune evasion. sEVs act as natural delivery vehicles of RNAs and can serve as useful targets for cancer therapy. This review article provides an overview of recent studies on TDEs and their RNA cargo, with emphasis on the role of these RNAs in carcinogenesis.

The Role of Intracellular and Extracellular Vesicles in the Development of Therapy Resistance in Cancer.

Cancer is the second leading cause of global mortality and claims approximately 10 million lives annually. Despite advances in treatments such as surgery, chemotherapy, and immunotherapy, resistance to these methods has emerged. Multidrug resistance (MDR), where cancer cells resist diverse treatments, undermines therapy effectiveness, escalating mortality rates. MDR mechanisms include, among others, drug inactivation, reduced drug uptake, enhanced DNA repair, and activation of survival pathways such as autophagy. Moreover, MDR mechanisms can confer resistance to other therapies like radiotherapy. Understanding these mechanisms is crucial for improving treatment efficacy and identifying new therapeutic targets. Extracellular vesicles (EVs) have gathered attention for their role in cancer progression, including MDR development through protein transfer and genetic reprogramming. Autophagy, a process balancing cellular resources, also influences MDR. The intersection of EVs and autophagy further complicates the understanding of MDR. Both extracellular (exosomes, microvesicles) and intracellular (autophagic) vesicles contribute to therapy resistance by regulating the tumor microenvironment, facilitating cell communication, and modulating drug processing. While much is known about these pathways, there is still a need to explore their potential for predicting treatment responses and understanding tumor heterogeneity.

Immunonutrition modulates tumor microenvironment and optimizes clinical outcomes in gastrointestinal cancer -a pilot study

Immunonutrition modulates tumor microenvironment and optimizes clinical outcomes in gastrointestinal cancer -a pilot study

Tumor-derived Exosomes and Antitumor Immunity.

Cancer immunotherapy, including immune checkpoint blockade, has been approved for treatment of patients with many cancer types. However, some patients fail to respond to immunotherapy, and emerging evidence indicates that tumor-derived exosomes (TEX) play a major role in reprogramming the host immune cells by inducing their dysfunction. Focusing on effector T cells, this review illustrates mechanisms of suppression that TEX use, thus promoting tumor escape from the host immune system. TEX carry multiple suppressive signals that drive T cell dysfunction and convert the tumor microenvironment into "an immune desert" in which activated T cells either die or are reprogrammed to mediate protumor functions. The reprogrammed T cells produce a new crop of CD3+ immunoinhibitory exosomes that further amplify suppression mediated by TEX. The result is a profound depletion of antitumor immune effector cells that reflects the defective immune competence of the cancer patient and partly explains why TEX are a significant barrier for cancer immunotherapy.

Construction and validation of a pancreatic cancer prognostic model based on genes related to the hypoxic tumor microenvironment

BACKGROUND Pancreatic cancer is one of the most lethal malignancies, characterized by poor prognosis and low survival rates. Traditional prognostic factors for pancreatic cancer offer inadequate predictive accuracy, often failing to capture the complexity of the disease. The hypoxic tumor microenvironment has been recognized as a significant factor influencing cancer progression and resistance to treatment. This study aims to develop a prognostic model based on key hypoxia-related molecules to enhance prediction accuracy for patient outcomes and to guide more effective treatment strategies in pancreatic cancer. AIM To develop and validate a prognostic model for predicting outcomes in patients with pancreatic cancer using key hypoxia-related molecules. METHODS This pancreatic cancer prognostic model was developed based on the expression levels of the hypoxia-associated genes CAPN2 , PLAU , and CCNA2 . The results were validated in an independent dataset. This study also examined the correlations between the model risk score and various clinical features, components of the immune microenvironment, chemotherapeutic drug sensitivity, and metabolism-related pathways. Real-time quantitative PCR verification was conducted to confirm the differential expression of the target genes in hypoxic and normal pancreatic cancer cell lines. RESULTS The prognostic model demonstrated significant predictive value, with the risk score showing a strong correlation with clinical features: It was significantly associated with tumor grade (G) (bP < 0.01), moderately associated with tumor stage (T) (aP < 0.05), and significantly correlated with residual tumor (R) status (bP < 0.01). There was also a significant negative correlation between the risk score and the half-maximal inhibitory concentration of some chemotherapeutic drugs. Furthermore, the risk score was linked to the enrichment of metabolism-related pathways in pancreatic cancer. CONCLUSION The prognostic model based on hypoxia-related genes effectively predicts pancreatic cancer outcomes with improved accuracy over traditional factors and can guide treatment selection based on risk assessment.

Immunosuppressive tumor microenvironment in gastric signet-ring cell carcinoma

Immunosuppressive tumor microenvironment in gastric signet-ring cell carcinoma

Comprehensive analysis of NOTCH pathway with tumor environment in pancreatic adenocarcinoma

Abstract Objectives Pancreatic adenocarcinoma (PAAD) ranks among the most prevalent malignant neoplasms, and multiple pathways are involved in its pathogenesis, including the NOTCH pathway. However, the variable biological functions of the pathway in PAAD are controversial. Methods RNA-seq data for PAAD was analyzed using data from The Cancer Genome Atlas and Genotype-Tissue Expression databases. Utilizing Kaplan-Meier survival curves and Cox regression analyses, we examined the prognostic significance. The tumor microenvironment and immunotherapy responses were investigated using ssGSEA, ESTIMATE, and TIDE models. Functional enrichment analysis was used to explore gene functions. Results We identified NOTCH2, JAG1, NOTCH4, and DLL3 as high-priority members of the NOTCH pathway that modulates PAAD. Elevated NOTCH2 and JAG1 levels were markedly linked to reduced overall survival (OS), while increased NOTCH4 and DLL3 levels were significantly related to extended OS. Immune analyses showed that NOTCH-based scores were closely related to the immune microenvironment. NOTCH scores were not only closely correlated with tumor-infiltrating immune cells, but also with immunologically activated and immune checkpoint gene expression. The high NOTCH score group had a higher proportion of tumor-infiltrating immune cells and had better responses to immune checkpoint inhibitor therapy. Conclusions These data indicate that NOTCH2, JAG1, NOTCH4, and DLL3 could function as efficient prognostic biomarkers and therapeutic targets in PAAD, and patients with a high NOTCH score may have a significant response to immune checkpoint inhibitor treatment.

Oncolytic adenovirus encoding decorin and CD40 ligand inhibits tumor growth and liver metastasis via immune activation in murine colorectal tumor model

Colorectal cancer (CRC) is the second common cause of cancer mortality worldwide, and it still lacks effective approaches for relapsed and metastatic CRC. Recently, oncolytic virus has been emerged as a promising immune therapeutic strategy. In this study, we develop a novel oncolytic adenovirus, rAd.mDCN.mCD40L, which drive oncolytic activity by telomerase reverse transcriptase promoter (TERTp). rAd.mDCN.mCD40L expressed both mouse genes of decorin (mDCN) and CD40 ligand (mCD40L), and produced effective cytotoxicity in both human and mouse CRC cells. Moreover, oncolytic adenovirus mediated mDCN over-expression inhibited Met expression in vitro. In CT26 subcutaneous tumor model, intratumorally delivery of oncolytic adenoviruses could inhibit tumor growth and liver metastasis, while mDCN and/or mCD40L armed oncolytic adenoviruses produced much more impressive responses. No obvious toxicity was detected in lung, liver and spleen. Moreover, mDCN and/or mCD40L armed oncolytic adenoviruses altered the immune state to activate anti-tumor responses, including increasing CD8+ T effector cells and CD4+ memory T cells, reducing MDSCs and Tregs in peripheral blood. Furthermore, mDCN and/or mCD40L armed oncolytic adenoviruses mediated mDCN and/or mCD40L expression in tumors, and up-regulated Th1 cytokines and reduced Th2 cytokines in tumors, which will be benefit for remodeling tumor microenvironment. Importantly, rAd.mDCN.mCD40L and rAd.mCD40L prevented tumor liver metastasis much more effectively than rAd.Null and rAd.mDCN. Therefore, rAd.mDCN.mCD40L and rAd.mCD40L are promising approaches for CRC therapy.

Abstract C120: Characterization of the inflammatory tumor microenvironment and its association with cancer health disparities

Abstract C120: Characterization of the inflammatory tumor microenvironment and its association with cancer health disparities

Abstract C080: Glioma cell-mediated hyper-thrombotic tumor microenvironment drives glioblastoma growth

Abstract C080: Glioma cell-mediated hyper-thrombotic tumor microenvironment drives glioblastoma growth

Abstract A061: The impact of race and obesity on the prostate tumor microenvironment

Abstract A061: The impact of race and obesity on the prostate tumor microenvironment

Mesenchymal stem cells in tumor microenvironment: drivers of bladder cancer progression through mitochondrial dynamics and energy production

Mesenchymal stem cells (MSCs) in tumor microenvironment (TME) are crucial for the initiation, development, and metastasis of cancer. The impact and mechanism of MSCs on bladder cancer are uncertain. Here we analyzed 205 patient samples to explore the relationships between tumor-stroma ratio and clinicopathological features. A co-culture model and nude mouse transplantation were used to explore the biological roles and molecular mechanisms of MSCs on bladder cancer cells. We found that a high tumor-stroma ratio was significantly associated with a larger tumor size and higher T stage, pathological grade, number of vascular invasions, and poor overall survival. MSCs in TME promoted the ability of bladder cancer cells to proliferate, migrate, and invade in vitro and in vivo. Next, we demonstrated that MSCs enhance mitochondrial autophagy and mitochondrial biogenesis of bladder cancer cells, and increase energy production, thereby promoting bladder cancer cell progression. Kynurenine (Kyn) produced by MSCs could enhance mitochondrial function by activating the AMPK pathway. IDO1 inhibitor could reverse the tumor‑promoting effects of MSCs in vitro and in vivo. Our results demonstrated that tryptophan metabolites Kyn of MSCs in TME could enhance mitochondrial function by activating the AMPK pathway, thereby promoting bladder cancer cell progression.