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Effect of FAO and OXPHOS on Tregs. AMPK in Tregs promotes FAO by increasing the expression of CPT1A. PD-1 on the surface of Tregs also promotes FAO by increasing CPT1A expression. Foxp3 promotes OXPHOS by increasing the expression of mitochondria-associated proteins, ROS, a by-product of OXPHOS, stabilizes NFAT in the nucleus and binds to CNS2 to promote Foxp3 expression
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Abstract Recent studies have shown that on one hand, tumors need to obtain a sufficient energy supply, and on the other hand they must evade the body’s immune surveillance. Because of their metabolic reprogramming characteristics, tumors can modify the physicochemical properties of the microenvironment, which in turn affects the biological characte...
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Context 1
... from fatty acid-induced apoptosis [85]. Metabolic re- active oxygen species (ROS) produced during the OXPHOS process also stabilize the transcription factor-activated T cell nuclear factor (NFAT) in the nu- cleus [86], which binds to the non-coding sequence 2 (CNS2) of the enhancer upstream of the Foxp3 gene [87] and promotes its expression. (Fig. 4). Treg' metabolic reprogramming mainly inhibits gly- colysis and promotes FAO and OXPHOS, so that cells can adapt to changes in a tumor microenvironment with low glucose and high lactic acid and promote cell prolif- eration, differentiation and immune ...
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Introduction
Nowadays, it has been recognized that gut microbiome can indirectly modulate cancer susceptibility or progression. However, whether intratumor microbes are parasitic, symbiotic, or merely bystanders in breast cancer is not fully understood. Microbial metabolite plays a pivotal role in the interaction of host and microbe via regulating...
Glycolytic reprogramming is one of the most important features of cancer and plays an integral role in the progression of cancer. In cancer cells, changes in glucose metabolism meet the needs of self-proliferation, angiogenesis and lymphangiogenesis, metastasis, and also affect the immune escape, prognosis evaluation and therapeutic effect of cance...
Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, however many patients still do not respond to treatment. Optimal results might be obtained by targeting cancer cell metabolism to modulate the immunosuppressive tumor microenvironment. Here, we identify sphingosine kinase-1 (SK1) as a key regul...
Immunotherapy, especially PD-1/PD-L1 checkpoint blockade immunotherapy, has led tumor therapy into a new era. However, the vast majority of patients do not benefit from immunotherapy. One possible reason for this lack of response is that the association between tumors, immune cells and metabolic reprogramming in the tumor microenvironment affect tu...
Transforming growth factor-β (TGF-β) signaling has a paradoxical role in cancer progression, and it acts as a tumor suppressor in the early stages but a tumor promoter in the late stages of cancer. Once cancer cells are generated, TGF-β signaling is responsible for the orchestration of the immunosuppressive tumor microenvironment (TME) and supports...
Citations
... 4 Moreover, the subsequent hypoxic microenvironment created by limited perfusion leads to inhibition of effector-T cells via increased regulatory-T cell mediated mechanisms and leads to a profound effect on immunogenicity. 5 These immunologically "cold" tumors can evade the immune system and demonstrate poor response rates to immune checkpoint inhibition (ICI). ...
Despite improvements in overall cancer mortality, deaths related to pancreatic cancer continue to rise. Following first-line treatment, second-line options are significantly limited. Classically, first-line treatment consisted of either gemcitabine or 5-fluorouracil based systemic chemotherapy. Upon progression of disease or recurrence, subsequent second-line treatment is still gemcitabine or 5-fluorouracil based chemotherapy, depending on what was used in the first line and the timing of progression or recurrence. A better understanding of the molecular underpinnings of pancreatic adenocarcinoma (PDAC) has led to new treatment strategies including specifically targeting the desmoplastic stroma, cytokine signaling and actionable mutations. Furthermore, efforts are also directed to enhance the immunogenicity profile of PDAC’s well-established immunologically “cold” tumor microenvironment. More recently, the outstanding response rates of chimeric antigen receptor T (CAR-T) cells in hematologic malignancies, have led to clinical trials to evaluate the treatment modality in PDAC. In this review, we summarize recently presented clinical trials for metastatic pancreatic adenocarcinoma with novel treatment approaches in the second line and beyond.
... The first is to induce immunosuppressive cells, including regulatory T cells, myeloid-derived suppressor cells, dendritic cells, and M2 macrophages, aiming at gathering around the tumor, secreting immunosuppressive factors, and inactivating cytotoxic T lymphocytes, thereby increasing immune tolerance of tumor cells. [40][41][42] The second immunosuppressive mechanism entails overexpressing immunosuppressive molecules or their receptors, including PD-L1/PD-1, Galectin-9/Tim-3, IDO1, LAG-3, and cytotoxic T lymphocyte antigen-4 (CTLA-4). These molecules, commonly referred to as immune checkpoints (ICs), possess the ability to impede effector T lymphocyte activation, consequently resulting in tumor IE. 43 Moreover, ICs contribute significantly to immune homeostasis maintenance and autoimmunity prevention. ...
Background
Immunotherapy with checkpoint inhibitors, especially those targeting programmed death receptor 1 (PD-1)/PD-1 ligand (PD-L1), is increasingly recognized as a highly promising therapeutic modality for malignancies. Nevertheless, the efficiency of immune checkpoint blockade therapy in treating glioblastoma (GBM) is constrained. Hence, it is imperative to expand our comprehension of the molecular mechanisms behind GBM immune escape (IE).
Methods
Protein chip analysis was performed to screen aberrantly expressed OMA1 protein in PD-1 inhibitor sensitive or resistant GBM. Herein, public databases and bioinformatics analysis were employed to investigate the OMA1 and PD-L1 relation. Then, this predicted relation was verified in primary GBM cell lines through distinct experimental methods. To investigate the molecular mechanism behind OMA1 in immunosuppression, a series of experimental methods were employed, including Western blotting, co-immunoprecipitation (Co-IP), mass spectrometry (MS), immunofluorescence, immunohistochemistry, and qRT-PCR.
Results
Our findings revealed that OMA1 competitively binds to HSPA9 to induce mitophagy and mediates the IE of GBM. Data from TCGA indicated a significant correlation between OMA1 and immunosuppression. OMA1 promoted PD-L1 levels in primary cells from patients with GBM. Next, the results of Co-IP and MS conducted on GBM primary cells revealed that OMA1 interacts with HSPA9 and induces mitophagy. OMA1 promoted not only cGAS–STING activity by increasing mitochondrial DNA release but also PD-L1 transcription by activating cGAS–STING. Eventually, OMA1 has been found to induce immune evasion in GBM through its regulation of PD-1 binding and PD-L1 mediated T cell cytotoxicity.
Conclusions
The OMA1/HSPA9/cGAS/PD-L1 axis is elucidated in our study as a newly identified immune therapeutic target in GBM.
... Tregs are a highly suppressive subgroup of CD4 + T cells and the dominant composition of the immunosuppressive microenvironment. 21,32 Prior evidence suggested that Tregs frequencies in TME possessed prognostic properties in GC. 33 Therefore, understanding the molecular mechanism of lactate and Tregs infiltration is urgently needed to design therapies for target lactate signaling and Tregs. In the present study, tumor-derived lactate bound to its receptor GPR81 to promote Tregs infiltration by modulating p65 and CX3CL1 in SGC-7901 after transfected with siRNA against p65 (qPCR normalized to GAPDH, Western blot normalized to tubulin, n = 3 biological replicates). ...
Lactate plays an important role in shaping immune tolerance in tumor microenvironment (TME) and correlates with poor prognosis in various solid tumors. Overcoming the immune resistance in an acidic TME may improve the anti-tumor immunity. Here, this study elucidated that via G-protein-coupled receptor 81 (GPR81), lactate could modulate immune tolerance in TME by recruiting regulatory T cells (Tregs) in vitro and in vivo. A high concentration of lactate was detected in cell supernatant and tissues of gastric cancer (GC), which was modulated by lactic dehydrogenase A (LDHA). GPR81 was the natural receptor of lactate and was overexpressed in different GC cell lines and samples, which correlated with poor outcomes in GC patients. Lactate/GPR81 signaling could promote the infiltration of Tregs into TME by inducing the expression of chemokine CX3CL1. GPR81 deficiency could decrease the infiltration of Tregs into TME, thereby inhibiting GC progression by weakening the inhibition of CD8⁺T cell function in a humanized mouse model. In conclusion, targeting the lactate/GPR81 signaling may potentially serve as a critical process to overcome immune resistance in highly glycolytic GC.
... Recent research has shown that specific signaling molecules found within the tumor microenvironment, along with factors generated by immune cells and tumor cells, have the potential to initiate the reprogramming of exTregs (17,18). In the hypoxic, lowglucose, and high-lactic acid conditions of the tumor microenvironment, exTregs undergo metabolic adaptability through reprogramming, gradually transitioning towards an immunosuppressive phenotype (19)(20)(21). Furthermore, Foxp3, the most crucial transcription factor regulating Tregs, undergoes posttranslational modification involving methylation, acetylation, glycosylation, phosphorylation, and ubiquitination. ...
Overcoming the immunosuppressive tumor microenvironment and identifying widely used immunosuppressants with minimal side effects are two major challenges currently hampering cancer immunotherapy. Regulatory T cells (Tregs) are present in almost all cancer tissues and play an important role in preserving autoimmune tolerance and tissue homeostasis. The tumor inflammatory microenvironment causes the reprogramming of Tregs, resulting in the conversion of Tregs to immunosuppressive phenotypes. This process ultimately facilitates tumor immune escape or tumor progression. However, current systemic Treg depletion therapies may lead to severe autoimmune toxicity. Therefore, it is crucial to understand the mechanism of Treg reprogramming and develop immunotherapies that selectively target Tregs within tumors. This article provides a comprehensive review of the potential mechanisms involved in Treg cell reprogramming and explores the application of Treg cell immunotherapy. The interference with reprogramming pathways has shown promise in reducing the number of tumor-associated Tregs or impairing their function during immunotherapy, thereby improving anti-tumor immune responses. Furthermore, a deeper understanding of the mechanisms that drive Treg cell reprogramming could reveal new molecular targets for future treatments.
... A previous study showed that the subsets of KIRC with the highest T cell accumulation have the worst survival rates [68]. Treg cells infiltrate heavily in the tumor microenvironment, not only inhibiting tumor immunity but also promoting tumor proliferation, invasion, and metastasis [69]. Multiple studies reported increased Treg cell infiltration associated with poor prognosis in ccRCC [70,71]. ...
Purpose
BCL-2-associated athanogene 3 (BAG3) is an anti-apoptotic protein that plays an essential role in the onset and progression of multiple cancer types. However, the clinical significance of BAG3 in kidney renal clear cell carcinoma (KIRC) remains unclear.
Methods
Using Tumor IMmune Estimation Resource (TIMER), The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) database, we explored the expression, prognostic value, and clinical correlations of BAG3 in KIRC. In addition, immunohistochemistry (IHC) of HKH cohort further validated the expression of BAG3 in KIRC and its impact on prognosis. Gene Set Cancer Analysis (GSCA) was utilized to scrutinize the prognostic value of BAG3 methylation. Gene Ontology (GO) term analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene set enrichment analysis (GSEA) were used to identify potential biological functions of BAG3 in KIRC. Single-sample gene set enrichment analysis (ssGSEA) was performed to confirm the correlation between BAG3 expression and immune cell infiltration.
Results
BAG3 mRNA expression and protein expression were significantly downregulated in KIRC tissues compared to normal kidney tissues, associated with adverse clinical–pathological factors and poor clinical prognosis. Multivariate Cox regression analysis indicated that low expression of BAG3 was an independent prognostic factor in KIRC patients. GSEA analysis showed that BAG3 is mainly involved in DNA methylation and the immune-related pathways in KIRC. In addition, the expression of BAG3 is closely related to immune cell infiltration and immune cell marker set.
Conclusion
BAG3 might be a potential therapeutic target and valuable prognostic biomarker of KIRC and is closely related to immune cell infiltration.
... This conclusion can be drawn since Smad4 is used by Smad3 to enhance the expression of active genes, while TRIM33 is known to be used for the purpose of activation of expression of "inactive" genes [29]. In addition, TGF-β itself is known to induce differentiation of naïve T cells into immunosuppressive regulatory T cells (Tregs) [30,31]. These mechanisms are schematically summarised in the Fig. 8. ...
Malignant transformation of human cells is associated with their re-programming which results in uncontrolled proliferation and in the same time biochemical activation of immunosuppressive pathways which form cancer immune evasion machinery. However, there is no conceptual understanding of whether immune evasion machinery pathways and expression of immune checkpoint proteins form a part of the process of malignant transformation or if they are triggered by T lymphocytes and natural killers (NK) attempting to attack cells which are undergoing or already underwent malignant transformation. To address this fundamental question, we performed experimental malignant transformation of BEAS-2B human bronchial epithelium cells and RC-124 non-malignant human kidney epithelial cells using bracken extracts containing carcinogenic alkaloid called ptaquiloside. This transformation led to a significant upregulation of cell proliferation velocity and in the same time led to a significant upregulation in expression of key immune checkpoint proteins – galectin-9, programmed death ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO1). Their increased expression levels were in line with upregulation of the levels and activities of HIF-1 transcription complex and transforming growth factor beta type 1 (TGF-β)-Smad3 signalling pathway. When co-cultured with T cells, transformed epithelial cells displayed much higher and more efficient immune evasion activity compared to original non-transformed cells. Therefore, this work resolved a very important scientific and clinical question and suggested that cancer immune evasion machinery is activated during malignant transformation of human cells regardless the presence of immune cells in microenvironment.
... [100] However, tumor cells often evade immune attack by upregulating immunosuppressive molecules and recruiting various immunosuppressive cells. [101] Recent research indicated that PDT could trigger an ICD cascade to elevate tumor sensitivity towards immunotherapy. [102] Therefore, the combination of PDT and immune modulators has become a feasible strategy to boost antitumor immunity by reversing tumor immunosuppressive environment. ...
Nowadays, cancer has become the leading cause of death worldwide, driving the need for effective therapeutics to improve patient prognosis. Photodynamic therapy (PDT) has been widely applied as an antitumor modality, owing to its minimal invasiveness, localized tumor damage, and high safety profile. However, its efficacy is limited by poor stability of photosensitizers, inadequate tumor accumulation, and a complex tumor microenvironment. To overcome these challenges, extensive endeavors have been made to explore the co‐assembly of the widely used photosensitizer chlorin e6 (Ce6) with various functional small molecules to enhance pharmacodynamic activity. This review provides a comprehensive overview of current studies on Ce6‐based nanoparticles for effective PDT and precise delivery of functional molecules. The self‐assembly mechanism will be discussed in detail, with a focus on potential strategies for combinational therapy with PDT.
... The acidic micro-environment caused by lactate accumulation in extracellular surroundings plays a crucial role in the anti-tumor immune response. Tregs are a highly suppressive subgroup of CD4 + T cells and the dominant composition of the immunosuppressive micro-environment [21,32]. Prior evidence suggested that Tregs frequencies in TME possessed prognostic properties in GC [33]. ...
Lactate plays an important role in shaping immune tolerance in tumor microenvironment (TME) and correlates with poor prognosis in various solid tumors. Overcoming the immune resistance in an acidic TME may improve the anti-tumor immunity. Here, this study elucidated that via G-protein-coupled receptor 81 (GPR81), lactate could modulate immune tolerance in TME by recruiting regulatory T cells (Tregs) in vitro and in vivo. A high concentration of lactate was detected in cell supernatant and tissues of gastric cancer (GC), which was modulated by lactic dehydrogenase A (LDHA). GPR81 was the natural receptor of lactate and was overexpressed in different GC cell lines and samples, which correlated with poor outcomes of GC patients. Lactate/GPR81 signaling could promote the infiltration of Tregs into TME by inducing the expression of chemokine CX3CL1. While GPR81-deficiency could decrease the infiltration of Tregs into TME, thereby inhibiting GC progression by weakening the inhibition of CD8 ⁺ T cell function in a humanized mouse model. In conclusion, targeting the lactate/GPR81 signaling may potentially serve as a critical process to overcome immune resistance in a highly glycolytic GC
... At single cell resolution, TUBB2A expressed across five cell clusters, including CD4Tconv, CD8T, CD8Tex, TProlif, and Tregs, all of which were T cells, further validating TUBB2A's correlation with T cell recruiting. Tumor microenvironment in TNBC reprograms Tregs by exerting immunosupressive effects [36], and finally tends to drug resistance [37]. We also found that TUBB2A inhibited CD8 + T cells, naive CD4 + T cells and activated memory CD4 + T cells according to immune infiltration analysis. ...
Objective
Triple negative breast cancer (TNBC) is a malignant subtype of breast cancer characterized by the absence of ER, PR, and HER2. We aimed to explore target gene from the perspective of cancer-immunity cycle, providing insights into treatment of TNBC.
Methods
We obtained TNBC samples from METABRIC database and downloaded 4 datasets from GEO database, as well as an IMvigor210 dataset. WGCNA was applied to screen genes associated with cancer-immunity cycle in TNBC. GO, KEGG and GSEA analyses were performed to explore the target gene’s potential functions and pathways. The binding motifs with transcription factors were predicted with FIMO. Immune infiltration analysis was conducted by CIBERSORT.
Results
TUBB2A was screened out as our target gene which was negatively correlated with T cell recruitment in cancer-immunity cycle. TUBB2A expressed higher in TNBC samples than in normal samples. High expression of TUBB2A was associated with poor prognosis of TNBC. 12 transcription factors and 5 miRNAs might regulate TUBB2A’s expression. The infiltration ratios of 7 types of immune cells such as CD8⁺ T cells, naive CD4⁺ T cells and activated memory CD4⁺ T cells were significantly lower in TUBB2A high expression group. TUBB2A was a potential drug target.
Conclusion
We screened a cancer-immunity cycle-related gene TUBB2A which was negatively correlated with T cell recruiting in TNBC. TUBB2A expressed higher in TNBC samples than in normal samples, associated with poor prognosis.
... Відомо, що Т-регуляторні клітини (Трег) є одним із найголовніших складових елементів супресорної ланки ІС ссавців [12]. Ці клітини продукують протизапальні медіатори та цитокіни (ІЛ-10, ІЛ-35, TРФ-, galectin-1 тощо) або чинять пряму цитотоксичну дію відносно ефекторних клітин шляхом продукції гранзиму В і перфоринів [13]. Відомо, що розвиток таких АІЗ, як РА, розсіяний склероз, хвороби кишківника, системний червоний вовчак та інші, супроводжує гіперпродукція запального ІЛ-17 Th17-клітинами [14]. ...
Проблематика. Однією з головних причин розвитку ревматоїдного артриту вважається порушення природної толерантності імунної системи до власних антигенів, що супроводжується розбалансуванням цитокінового профілю організму. Перспективним методом корекції такого стану є реабілітація антиген-специфічної толерантності, у формуванні якої беруть участь толерогенні дендритні клітини (толДК). Мета. Експериментальне обґрунтування можливості коригування цитокінового профілю тварин з ад’ювантним артритом (АА) шляхом застосування толДК із кріоконсервованих попередників кісткового мозку. Методика реалізації. Дослідження проводили на мишах лінії СВА/Н. Розвиток АА оцінювали за клінічним показником – індексом артриту. Визначали вміст про- (ФНО-a, ІЛ-6, ІФН-g) і протизапальних (ІЛ-10, ІЛ-4) цитокінів у сироватці крові тварин з АА до та після введення толДК, отриманих із нативних (НатДК) або кріоконсервованих (КріоДК) за різними режимами мононуклеарів (МНК) кісткового мозку. На 14-ту добу після індукції АА тваринам внутрішньовенно вводили толДК (5´105 клітин на мишу). Через тиждень оцінювали вміст цитокінів у сироватці крові тварин та індекс артриту. Результати. За розвитку АА спостерігалося односпрямоване підвищення рівня ФНП-a і ІЛ-6 і зниження вмісту протизапальних цитокінів, що супроводжувалося набряком суглобів тварин. КріоДК мали більший коригувальний ефект відносно про- і протизапальних цитокінів порівняно з НатДК, що підтверджено зниженням індексу артриту як клінічного прояву патології. Висновки. Доведено можливість корекції порушеного цитокінового профілю та клінічного стану тварин при розвитку АА шляхом застосування толДК, що отримані з кріоконсервованих МНК кісткового мозку. Відпрацьовано певні умови кріоконсервування МНК, що забезпечують формування з них толДК із більш потужною здатністю порівняно з похідними нативних МНК до коригування цитокінового профлю та клінічного статусу тварин з АА.
