Chromatin accessibility of CD8 T cell differentiation and metabolic regulation.
TL;DR: Different chromatin openness of CD8 + T cell states is associated with metabolic regulation and the high accessibility of upstream binding site SP1 emerged as critical transcription factor for both Teff and Tmem in fatty acid oxidation (FAO) and glycolysis.
Abstract: CD8+T cells play an important role in controlling infections and tumorigenesis in vivo. naive CD8+T cells exponentially expand and exert effector functions in response to TCR ligation. After antigen clearance, most effector CD8+T cells (Teff) experience activation-induced cell death, only a small portion becomes long-lived memory T cells (Tmem). The cell-intrinsic mechanisms driving the differentiation need further understanding. Here we used combined transposase-accessible chromatin (ATAC-seq) technology and RNA-seq analysis to explore chromatin accessibility in CD8+T cell subsets (naive T cells, Teff, and Tmem). The data demonstrates different chromatin openness of CD8+T cell states is associated with metabolic regulation and the high accessibility of upstream binding site SP1 emerged as critical transcription factor for both Teff and Tmem in fatty acid oxidation (FAO) and glycolysis. The different presence of accessible regions in CD8+T cell subsets provides a novel perspective for understanding epigenetic mechanisms underlying T cell differentiation and related immune response.
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TL;DR: The overlapping metabolic reprogramming of cancer and immune cells is a putative determinant of the antitumor immune response in cancer Increased evidence suggests that cancer metabolism not only plays a crucial role in cancer signaling for sustaining tumorigenesis and survival, but also has wider implications in the regulation of the immune response through both the release of metabolites and affecting the expression of immune molecules, such as lactate, PGE2, arginine, etc.
Abstract: The overlapping metabolic reprogramming of cancer and immune cells is a putative determinant of the antitumor immune response in cancer Increased evidence suggests that cancer metabolism not only plays a crucial role in cancer signaling for sustaining tumorigenesis and survival, but also has wider implications in the regulation of antitumor immune response through both the release of metabolites and affecting the expression of immune molecules, such as lactate, PGE2, arginine, etc Actually, this energetic interplay between tumor and immune cells leads to metabolic competition in the tumor ecosystem, limiting nutrient availability and leading to microenvironmental acidosis, which hinders immune cell function More interestingly, metabolic reprogramming is also indispensable in the process of maintaining self and body homeostasis by various types of immune cells At present, more and more studies pointed out that immune cell would undergo metabolic reprogramming during the process of proliferation, differentiation, and execution of effector functions, which is essential to the immune response Herein, we discuss how metabolic reprogramming of cancer cells and immune cells regulate antitumor immune response and the possible approaches to targeting metabolic pathways in the context of anticancer immunotherapy We also describe hypothetical combination treatments between immunotherapy and metabolic intervening that could be used to better unleash the potential of anticancer therapies
214 citations
TL;DR: Current comprehension of metabolic reprogramming of CAFs and immune cells and crosstalk between them that induces immune responses, and their contributions to tumorigenesis and progression are discussed.
Abstract: It is notorious that cancer cells alter their metabolism to adjust to harsh environments of hypoxia and nutritional starvation. Metabolic reprogramming most often occurs in the tumor microenvironment (TME). TME is defined as the cellular environment in which the tumor resides. This includes surrounding blood vessels, fibroblasts, immune cells, signaling molecules and the extracellular matrix (ECM). It is increasingly recognized that cancer cells, fibroblasts and immune cells within TME can regulate tumor progression through metabolic reprogramming. As the most significant proportion of cells among all the stromal cells that constitute TME, cancer-associated fibroblasts (CAFs) are closely associated with tumorigenesis and progression. Multitudinous studies have shown that CAFs participate in and promote tumor metabolic reprogramming and exert regulatory effects via the dysregulation of metabolic pathways. Previous studies have demonstrated that curbing the substance exchange between CAFs and tumor cells can dramatically restrain tumor growth. Emerging studies suggest that CAFs within the TME have emerged as important determinants of metabolic reprogramming. Metabolic reprogramming also occurs in the metabolic pattern of immune cells. In the meanwhile, immune cell phenotype and functions are metabolically regulated. Notably, immune cell functions influenced by metabolic programs may ultimately lead to alterations in tumor immunity. Despite the fact that multiple previous researches have been devoted to studying the interplays between different cells in the tumor microenvironment, the complicated relationship between CAFs and immune cells and implications of metabolic reprogramming remains unknown and requires further investigation. In this review, we discuss our current comprehension of metabolic reprogramming of CAFs and immune cells (mainly glucose, amino acid, and lipid metabolism) and crosstalk between them that induces immune responses, and we also highlight their contributions to tumorigenesis and progression. Furthermore, we underscore potential therapeutic opportunities arising from metabolism dysregulation and metabolic crosstalk, focusing on strategies targeting CAFs and immune cell metabolic crosstalk in cancer immunotherapy.
13 citations
TL;DR: A computational framework is presented to help illustrate the potential of somatic gene mutations in shaping the tumor immune microenvironment and highlighted the predictive capacity of gene mutations that are positively associated with CD8 T cells for the clinical benefit of immunotherapy.
Abstract: Interaction between tumor cells and immune cells determined highly heterogeneous microenvironments across patients, leading to substantial variation in clinical benefits from immunotherapy. Somatic gene mutations were found not only to elicit adaptive immunity but also to influence the composition of tumor immune microenvironment and various processes of antitumor immunity. However, due to an incomplete view of associations between gene mutations and immunophenotypes, how tumor cells shape the immune microenvironment and further determine the clinical benefit of immunotherapy is still unclear. To address this, we proposed a computational approach, inference of mutation effect on immunophenotype by integrated gene set enrichment analysis (MEIGSEA), for tracing back the genomic factor responsible for differences in immunophenotypes. MEIGSEA was demonstrated to accurately identify the previous confirmed immune-associated gene mutations, and systematic evaluation in simulation data further supported its performance. We used MEIGSEA to investigate the influence of driver gene mutations on the infiltration of 22 immune cell types across 19 cancers from The Cancer Genome Atlas. The top associated gene mutations with infiltration of CD8 T cells, such as CASP8, KRAS and EGFR, also showed extensive impact on other immune components; meanwhile, immune effector cells shared critical gene mutations that collaboratively contribute to shaping distinct tumor immune microenvironment. Furthermore, we highlighted the predictive capacity of gene mutations that are positively associated with CD8 T cells for the clinical benefit of immunotherapy. Taken together, we present a computational framework to help illustrate the potential of somatic gene mutations in shaping the tumor immune microenvironment.
4 citations
TL;DR: In this paper , a computational approach, inference of mutation effect on immunophenotype by integrated gene set enrichment analysis (MEIGSEA), for tracing back the genomic factor responsible for differences in immunophenotypes was proposed.
Abstract: Interaction between tumor cells and immune cells determined highly heterogeneous microenvironments across patients, leading to substantial variation in clinical benefits from immunotherapy. Somatic gene mutations were found not only to elicit adaptive immunity but also to influence the composition of tumor immune microenvironment and various processes of antitumor immunity. However, due to an incomplete view of associations between gene mutations and immunophenotypes, how tumor cells shape the immune microenvironment and further determine the clinical benefit of immunotherapy is still unclear. To address this, we proposed a computational approach, inference of mutation effect on immunophenotype by integrated gene set enrichment analysis (MEIGSEA), for tracing back the genomic factor responsible for differences in immunophenotypes. MEIGSEA was demonstrated to accurately identify the previous confirmed immune-associated gene mutations, and systematic evaluation in simulation data further supported its performance. We used MEIGSEA to investigate the influence of driver gene mutations on the infiltration of 22 immune cell types across 19 cancers from The Cancer Genome Atlas. The top associated gene mutations with infiltration of CD8 T cells, such as CASP8, KRAS and EGFR, also showed extensive impact on other immune components; meanwhile, immune effector cells shared critical gene mutations that collaboratively contribute to shaping distinct tumor immune microenvironment. Furthermore, we highlighted the predictive capacity of gene mutations that are positively associated with CD8 T cells for the clinical benefit of immunotherapy. Taken together, we present a computational framework to help illustrate the potential of somatic gene mutations in shaping the tumor immune microenvironment.
3 citations
TL;DR: In this paper , the authors reported that accumulation of BCAAs in CD8+ T cells due to the impairment of BCAA degradation in 2C-type serine/threonine protein phosphatase (PP2Cm)-deficient mice leads to hyperactivity of T cells and enhanced anti-tumor immunity.
1 citations
References
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TL;DR: A brief refresher course on six of the major metabolic pathways involved in immunometabolism is provided, giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response.
Abstract: Immunometabolism is emerging an important area of immunological research, but for many immunologists the complexity of the field can be daunting. Here, the authors provide an overview of six key metabolic pathways that occur in immune cells and explain what is known (and what is still to be uncovered) concerning their effects on immune cell function. In recent years a substantial number of findings have been made in the area of immunometabolism, by which we mean the changes in intracellular metabolic pathways in immune cells that alter their function. Here, we provide a brief refresher course on six of the major metabolic pathways involved (specifically, glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism), giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response. What is emerging is a complex interplay between metabolic reprogramming and immunity, which is providing an extra dimension to our understanding of the immune system in health and disease.
1,857 citations
TL;DR: This review considers how TFs are identified and functionally characterized, principally through the lens of a catalog of over 1,600 likely human TFs and binding motifs for two-thirds of them, highlighting the importance of continued effort to understand TF-mediated gene regulation.
1,833 citations
"Chromatin accessibility of CD8 T ce..." refers background in this paper
...…the accessibility of transcription factors (TFs) to the DNA (Arttu et al. 2013), the genome of eukaryotic cells is tightly packaged into folded nucleosomes and the density near transcriptional control elements orchestrates specific genes expression (Lambert et al. 2018; Slattery et al. n.d.)....
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TL;DR: The results show that miR-10a may positively control global protein synthesis via the stimulation of ribosomal protein mRNA translation and ribosome biogenesis and hereby affect the ability of cells to undergo transformation.
1,352 citations
"Chromatin accessibility of CD8 T ce..." refers background in this paper
...5′UTR could play regulatory roles in RNA translation, RNA stability, and in RNA transcription (Ørom et al. 2008)....
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TL;DR: Over the past decade, the signalling pathways and transcriptional programmes that regulate the formation of heterogeneous populations of effector and memory CD8+ T cells have started to be characterized, and this Review discusses the major advances in these areas.
Abstract: During an infection, T cells can differentiate into multiple types of effector and memory T cells, which help to mediate pathogen clearance and provide long-term protective immunity. These cells can vary in their phenotype, function and location, and in their long-term fate in terms of their ability to populate the memory T cell pool. Over the past decade, the signalling pathways and transcriptional programmes that regulate the formation of heterogeneous populations of effector and memory CD8+ T cells have started to be characterized, and this Review discusses the major advances in these areas.
1,222 citations
TL;DR: Global analysis of the data revealed that homodimer orientation and spacing preferences, and base-stacking interactions, have a larger role in TF-DNA binding than previously appreciated.
1,140 citations
"Chromatin accessibility of CD8 T ce..." refers background in this paper
...After the interruption, VAHTS DNA clean beads were added to purify the fragment before PCR enrichment (14–15 cycles)....
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...Then added the transposase mix to break the DNA, and put the mixture in PCR at 37 °C for 30 min....
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...By controlling the accessibility of transcription factors (TFs) to the DNA (Arttu et al. 2013), the genome of eukaryotic cells is tightly packaged into folded nucleo-...
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...By controlling the accessibility of transcription factors (TFs) to the DNA (Arttu et al. 2013), the genome of eukaryotic cells is tightly packaged into folded nucleosomes and the density near transcriptional control elements orchestrates specific genes expression (Lambert et al. 2018; Slattery et…...
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...7b, c. SP1 encodes proteins involved in many cellular processes including cell differentiation, growth, apoptosis, immune response, and response to DNA damage (Saffer et al. 1991)....
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