Dataset Information

Ovarian Cancer Cells Promote Glycolysis Metabolism and TLR8-Mediated Metabolic Control of Human CD4+ T Cells.

ABSTRACT: An immunosuppressive microenvironment is a major obstacle for successful tumor immunotherapy. Elucidating the regulatory mechanisms of energy metabolism and functionality in CD4+ T cells will provide insights for the development of novel immunotherapies for ovarian cancer (OC). An Agilent microarray was used to detect differences in gene expression between peripheral CD4+ T cells from five OC patients and those from five healthy controls. Functional pathway analysis was performed for differentially expressed genes. Gene expression profiles revealed significant differences in expression levels of 5,175 genes in peripheral CD4+ T cells from five patients with OC. Functional analysis indicated that the most significantly enriched pathways were metabolic pathways. Furthermore, eight glycolysis-related genes all showed significantly increased expression in peripheral CD4+ T cells of OC patients. Moreover, we established a coculture system of human CD4+ T cells with the OC cell line SKOV3, and then treated them with toll-like receptor 8 (TLR8) ligand ssRNA 40. Coculturing with SKOV3 cells could increase the expression of the eight glycolysis-related genes, promote glucose uptake and glycolysis in CD4+ T cells, induce the differentiation of CD4+ CD25+ Foxp3+ T cells, and enhance the suppression of naïve CD4+ T cells. Additionally, activated TLR8 signaling could mediate the reprogramming of glycolysis metabolism and function in CD4+ T cells. Overall, our study indicates that the SKOV3 coculture environment could regulate the glycolysis metabolism and function of CD4+ T cells, and also that TLR8 mediated the metabolic control of glycolysis in CD4+ T cells cocultured with SKOV3 cells. This provides a new direction for immunotherapy investigations in OC.

SUBMITTER: Shang W

PROVIDER: S-EPMC7545320 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Ovarian Cancer Cells Promote Glycolysis Metabolism and TLR8-Mediated Metabolic Control of Human CD4+ T Cells.

Shang Wenwen W Xu Rui R Xu Ting T Wu Ming M Xu Juan J Wang Fang F

Frontiers in oncology 20200925

An immunosuppressive microenvironment is a major obstacle for successful tumor immunotherapy. Elucidating the regulatory mechanisms of energy metabolism and functionality in CD4+ T cells will provide insights for the development of novel immunotherapies for ovarian cancer (OC). An Agilent microarray was used to detect differences in gene expression between peripheral CD4+ T cells from five OC patients and those from five healthy controls. Functional pathway analysis was per ...[more]

PMID: 33102225

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Project description:In Type 1 Diabetes (T1D), CD4+ T cells initiate autoimmune attack of pancreatic islet β cells. Importantly, bioenergetic programs dictate T cell function, with specific pathways required for progression through the T cell lifecycle. During activation, CD4+ T cells undergo metabolic reprogramming to the less efficient aerobic glycolysis, similarly to highly proliferative cancer cells. In an effort to limit tumor growth in cancer, use of glycolytic inhibitors have been successfully employed in preclinical and clinical studies. This strategy has also been utilized to suppress T cell responses in autoimmune diseases like Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), and Rheumatoid Arthritis (RA). However, modulating T cell metabolism in the context of T1D has remained an understudied therapeutic opportunity. In this study, we utilized the small molecule PFK15, a competitive inhibitor of the rate limiting glycolysis enzyme 6-phosphofructo-2-kinase/fructose-2,6- biphosphatase 3 (PFKFB3). Our results confirmed PFK15 inhibited glycolysis utilization by diabetogenic CD4+ T cells and reduced T cell responses to β cell antigen in vitro. In an adoptive transfer model of T1D, PFK15 treatment delayed diabetes onset, with 57% of animals remaining euglycemic at the end of the study period. Protection was due to induction of a hyporesponsive T cell phenotype, characterized by increased and sustained expression of the checkpoint molecules PD-1 and LAG-3 and downstream functional and metabolic exhaustion. Glycolysis inhibition terminally exhausted diabetogenic CD4+ T cells, which was irreversible through restimulation or checkpoint blockade in vitro and in vivo. In sum, our results demonstrate a novel therapeutic strategy to control aberrant T cell responses by exploiting the metabolic reprogramming of these cells during T1D. Moreover, the data presented here highlight a key role for nutrient availability in fueling T cell function and has implications in our understanding of T cell biology in chronic infection, cancer, and autoimmunity.

Project description:The cardiovascular and immune systems undergo profound and intertwined alterations with aging. Recent studies have reported that an accumulation of memory and terminally differentiated T cells in elderly subjects can fuel myocardial aging and boost the progression of heart diseases. Nevertheless, it remains unclear whether the immunological senescence profile is sufficient to cause age-related cardiac deterioration or merely acts as an amplifier of previous tissue-intrinsic damage. Herein, we sought to decompose the causality in this cardio-immune crosstalk by studying young mice harboring a senescent-like expanded CD4+ T cell compartment. Thus, immunodeficient NSG-DR1 mice expressing HLA-DRB1*01:01 were transplanted with human CD4+ T cells purified from matching donors that rapidly engrafted and expanded in the recipients without causing xenograft reactions. In the donor subjects, the CD4+ T cell compartment was primarily composed of naïve cells defined as CCR7+CD45RO-. However, when transplanted into young lymphocyte-deficient mice, CD4+ T cells underwent homeostatic expansion, upregulated expression of PD-1 receptor and strongly shifted towards effector/memory (CCR7- CD45RO+) and terminally-differentiated phenotypes (CCR7-CD45RO-), as typically seen in elderly. Differentiated CD4+ T cells also infiltrated the myocardium of recipient mice at comparable levels to what is observed during physiological aging. In addition, young mice harboring an expanded CD4+ T cell compartment showed increased numbers of infiltrating monocytes, macrophages and dendritic cells in the heart. Bulk mRNA sequencing analyses further confirmed that expanding T-cells promote myocardial inflammaging, marked by a distinct age-related transcriptomic signature. Altogether, these data indicate that exaggerated CD4+ T-cell expansion and differentiation, a hallmark of the aging immune system, is sufficient to promote myocardial alterations compatible with inflammaging in juvenile healthy mice.

Dataset Information

Ovarian Cancer Cells Promote Glycolysis Metabolism and TLR8-Mediated Metabolic Control of Human CD4+ T Cells.

Publications

Ovarian Cancer Cells Promote Glycolysis Metabolism and TLR8-Mediated Metabolic Control of Human CD4<sup>+</sup> T Cells.

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