Regulatory T cells promote glioma cell stemness through TGF-β–NF-κB–IL6–STAT3 signaling

Li, Shasha; Zhang, Chaoqi; Wang, Boqiao; Zhang, Huanyu; Li, Congcong; Qin, Guohui; Cao, Lei; Gao, Qun; Ping, Yu; Zhang, Kai; Lian, Jingyao; Zhao, Qitai; Wang, Dan; Zhang, Zhen; Zhao, Xuan; Li, Yang; Huang, Lan; Yang, Bo; Zhang, Yi

doi:10.21203/rs.3.rs-46778/v1

Cited by 11 publications

(10 citation statements)

References 27 publications

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“…These poor prognostic correlations in patients is tied to the fact that T regulatory cells can suppress the function of T helper cells through the production of immunosuppressive cytokines, including IL-10 and TGF-b (68,69), secrete perforins and granzymes to directly destroy effector T cells and B cells (70), and express the checkpoint inhibitor CTLA-4 to suppress APC activity (71). There have also been reports of T regulatory cells directly increasing the growth of tumors through the stimulation of cancer stem cells via the NF-kB-IL6-STAT4 signaling axis (72).…”

Section: The Tumor Microenvironment and Tumor Associated Immune Cellsmentioning

confidence: 99%

Immunological Effects of Histotripsy for Cancer Therapy

et al. 2021

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Cancer is the second leading cause of death worldwide despite major advancements in diagnosis and therapy over the past century. One of the most debilitating aspects of cancer is the burden brought on by metastatic disease. Therefore, an ideal treatment protocol would address not only debulking larger primary tumors but also circulating tumor cells and distant metastases. To address this need, the use of immune modulating therapies has become a pillar in the oncology armamentarium. A therapeutic option that has recently emerged is the use of focal ablation therapies that can destroy a tumor through various physical or mechanical mechanisms and release a cellular lysate with the potential to stimulate an immune response. Histotripsy is a non-invasive, non-ionizing, non-thermal, ultrasound guided ablation technology that has shown promise over the past decade as a debulking therapy. As histotripsy therapies have developed, the full picture of the accompanying immune response has revealed a wide range of immunogenic mechanisms that include DAMP and anti-tumor mediator release, changes in local cellular immune populations, development of a systemic immune response, and therapeutic synergism with the inclusion of checkpoint inhibitor therapies. These studies also suggest that there is an immune effect from histotripsy therapies across multiple murine tumor types that may be reproducible. Overall, the effects of histotripsy on tumors show a positive effect on immunomodulation.

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Section: The Tumor Microenvironment and Tumor Associated Immune Cellsmentioning

confidence: 99%

Immunological Effects of Histotripsy for Cancer Therapy

et al. 2021

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“…MDSCs can mediate tumorinduced immune tolerance and secrete IL-6 [31]. Simultaneously, Treg cells can suppress the effector T cell responses through a variety of mechanisms [32]. High enrichment of MDSCs and Treg cells in glioma often indicates an immune suppressive microenvironment that promotes tumor progression and facilitates tumor immunity escape.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of homeobox 5 predicts poor prognosis: A potential therapeutic target for glioma

Xu¹,

Huang²,

Yang³

et al. 2021

Preprint

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Background: The homeobox gene 5 (HOXB5) encodes a transcription factor that regulates the central nervous system embryonic development. Of note, its expression pattern and prognostic role in glioma remain unelucidated. This study aimed to identify the relationship between HOXB5 and glioma by investigating the HOXB5 expression data from the The Cancer Genome Atlas (TCGA) and The Genotype Tissue Expression (GTEx) databases and validating the obtained data using the Chinese Glioma Genome Atlas (CGGA) database. Kaplan-Meier and univariate cox regression analyses were performed to assess the prognostic value of HOXB5. The key functions and signaling pathways of HOXB5 were analyzed using GSEA and GSVA. Immune infiltration was calculated using Microenvironment Cell Populations-counter (MCP-counter), single-sample Gene Set Enrichment Analysis (ssGSEA), and ESTIMATE algorithms.Result: HOXB5 expression was elevated in glioma tissues. The increased levels of HOXB5 were significantly correlated with a higher WHO grade and aggressive cancer phenotypes. HOXB5 overexpression represented a risk factor that was associated with shorter overall survival (OS) while exhibiting a moderate forecast efficiency in most clinical subgroups. These results were validated using the CGGA and Rembrandt datasets. Furthermore, the functional analysis showed enrichment of angiogenesis, the IL6/JAK-STAT3 pathway, and inflammatory response in the tissues that showed high expression of HOXB5. Lastly, the high expression of HOXB5 was associated with enrichment of Tregs and MDSCs, and HOXB5 expression was shown to play a role in several immune checkpoint genes.Conclusions: HOXB5 may serve as a predictive factor of glioma malignancy and prognostic status and represents potential as a molecular treatment candidate.

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“…137 Regulatory T cells (Tregs) in GSC niches produce IL-6 and promote GSC stemness via IL-6-STAT3 signaling. 143 Effects of inhibition of STAT3 on stemness of GSCs are presently being investigated. [144][145][146][147] Abbreviations: OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species; GSCs, glioblastoma stem cells.…”

Section: Box 8 Signal Transducer and Activator Of Transcription 3 (Stat3)mentioning

confidence: 99%

Cell Biology Meets Cell Metabolism: Energy Production Is Similar in Stem Cells and in Cancer Stem Cells in Brain and Bone Marrow

Noorden

Breznik

Novak

et al. 2021

J Histochem Cytochem.

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Energy production by means of ATP synthesis in cancer cells has been investigated frequently as a potential therapeutic target in this century. Both (an)aerobic glycolysis and oxidative phosphorylation (OXPHOS) have been studied. Here, we review recent literature on energy production in glioblastoma stem cells (GSCs) and leukemic stem cells (LSCs) versus their normal counterparts, neural stem cells (NSCs) and hematopoietic stem cells (HSCs), respectively. These two cancer stem cell types were compared because their niches in glioblastoma tumors and in bone marrow are similar. In this study, it became apparent that (1) ATP is produced in NSCs and HSCs by anaerobic glycolysis, whereas fatty acid oxidation (FAO) is essential for their stem cell fate and (2) ATP is produced in GSCs and LSCs by OXPHOS despite the hypoxic conditions in their niches with FAO and amino acids providing its substrate. These metabolic processes appeared to be under tight control of cellular regulation mechanisms which are discussed in depth. However, our conclusion is that systemic therapeutic targeting of ATP production via glycolysis or OXPHOS is not an attractive option because of its unwanted side effects in cancer patients.

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Regulatory T cells promote glioma cell stemness through TGF-β–NF-κB–IL6–STAT3 signaling

Cited by 11 publications

References 27 publications

Immunological Effects of Histotripsy for Cancer Therapy

Immunological Effects of Histotripsy for Cancer Therapy

Increased expression of homeobox 5 predicts poor prognosis: A potential therapeutic target for glioma

Cell Biology Meets Cell Metabolism: Energy Production Is Similar in Stem Cells and in Cancer Stem Cells in Brain and Bone Marrow

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