Natural Genetic Variation Reveals Key Features of Epigenetic and Transcriptional Memory in Virus-Specific CD8 T Cells

Veeken, Joris van der; Zhong, Yi; Sharma, Roshan; Mažutis, Linas; Dao, Phuong; Pe’er, Dana; Leslie, Christina; Rudensky, Alexander Y.

doi:10.1016/j.immuni.2019.03.031

Cited by 54 publications

(53 citation statements)

References 82 publications

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“…For example, this model may be useful in interrogating additional mechanisms by which these cohabiting, inbred mice respond differently to therapeutic interventions in tumors. Studies suggest that even though inbred mouse strains were created to be essentially genetically identical, these mice are made through many generations of brother-sister mating, and minor variations can arise over time that could create differences in the host immune responses (68,69). Performing whole genome sequencing in this model could be useful for addressing the contributions of minor genetic variations to the responder versus nonresponder phenotype.…”

Section: Discussionmentioning

confidence: 99%

A bilateral tumor model identifies transcriptional programs associated with patient response to immune checkpoint blockade

Chen

Newcomer

Pauken

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Immune checkpoint blockade (ICB) is efficacious in many diverse cancer types, but not all patients respond. It is important to understand the mechanisms driving resistance to these treatments and to identify predictive biomarkers of response to provide best treatment options for all patients. Here we introduce a resection and response-assessment approach for studying the tumor microenvironment before or shortly after treatment initiation to identify predictive biomarkers differentiating responders from nonresponders. Our approach builds on a bilateral tumor implantation technique in a murine metastatic breast cancer model (E0771) coupled with anti-PD-1 therapy. Using our model, we show that tumors from mice responding to ICB therapy had significantly higher CD8+ T cells and fewer Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs) at early time points following therapy initiation. RNA sequencing on the intratumoral CD8+ T cells identified the presence of T cell exhaustion pathways in nonresponding tumors and T cell activation in responding tumors. Strikingly, we showed that our derived response and resistance signatures significantly segregate patients by survival and associate with patient response to ICB. Furthermore, we identified decreased expression of CXCR3 in nonresponding mice and showed that tumors grown in Cxcr3−/− mice had an elevated resistance rate to anti-PD-1 treatment. Our findings suggest that the resection and response tumor model can be used to identify response and resistance biomarkers to ICB therapy and guide the use of combination therapy to further boost the antitumor efficacy of ICB.

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Section: Discussionmentioning

confidence: 99%

A bilateral tumor model identifies transcriptional programs associated with patient response to immune checkpoint blockade

Chen

Newcomer

Pauken

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…From a more general perspective, the intimate link between T-bet and chromatin modifications is underlined by a recent study exploring chromatin and gene expression changes associated with viral infection in mouse CD8 T cells. The authors reported that T-box and Runx genes have been shown to act as critical mediators of chromatin remodeling during CD8 T cell activation (27).…”

Section: T-bet-ifn-γ Pathwaymentioning

confidence: 99%

NK Cell Function Regulation by TGF-β-Induced Epigenetic Mechanisms

et al. 2020

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TGF-β is a potent immunosuppressive cytokine that severely affects the function of NK cells. Tumor cells can take advantage of this ability, enriching their surrounding microenvironment with TGF-β. TGF-β can alter the expression of effector molecules and of activating and chemokine receptors, influence metabolism, induce the NK cell conversion toward the less cytolytic ILC1s. These and other changes possibly occur by the induction of complex gene expression programs, involving epigenetic mechanisms. While most of these programs are at present unexplored, the role of certain transcription factors, microRNAs and chromatin changes determined by TGF-β in NK cells start to be elucidated in human and/or mouse NK cells. The deep understanding of these mechanisms will be useful to design therapies contributing to restore the full NK function.

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“…Van der Veeken et al. linked genetic variation to allelic imbalances in chromatin accessibility to reveal the contribution of specific TF DNA-binding motifs to stable and transient gene regulation in CD8 T cells responding to acute viral infection [ 89 ]. They identified some stably responsive DNA elements that were characterised by chromatin remodelling events affecting different neighbouring sites and requiring distinct TF-binding motifs for their co-operations in virus-specific CD8 T cells.…”

Section: Do Enhancer Snps Influence the Inflammatory Response In Diabmentioning

confidence: 99%

“…They identified some stably responsive DNA elements that were characterised by chromatin remodelling events affecting different neighbouring sites and requiring distinct TF-binding motifs for their co-operations in virus-specific CD8 T cells. Interestingly, transiently regulated regions had a higher degree of constitutive accessibility than stably regulated peaks, and relatively minor changes were induced by activation [ 89 ]. As discussed previously, important chromatin remodelling events are associated with stability across several cell types and experimental systems.…”

Section: Do Enhancer Snps Influence the Inflammatory Response In Diabmentioning

confidence: 99%

“…Enhancer remodelling and chromatin dynamics in Treg cells, natural killer (NK) cells, and macrophages respond in a similar manner to inflammatory challenges [ 72 ]. Moreover, polymorphisms analysed in different mouse strains have been used to identify TFs cooperating with macrophage lineage-determining TFs [ 89 ]. Thus, this study provides insights into the molecular mechanisms driving virus-specific CD8 T cell responses but also suggests a general mechanism for the formation of transcriptional and epigenetic memory applicable to other immune and non-immune cells [ 89 ].…”

Section: Do Enhancer Snps Influence the Inflammatory Response In Diabmentioning

confidence: 99%

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Regulation of inflammation in diabetes: From genetics to epigenomics evidence

Diedisheim

Carcarino

Vandiedonck

et al. 2020

Molecular Metabolism

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Background Diabetes is one of the greatest public health challenges worldwide, and we still lack complementary approaches to significantly enhance the efficacy of preventive and therapeutic approaches. Genetic and environmental factors are the culprits involved in diabetes risk. Evidence from the last decade has highlighted that deregulation in the immune and inflammatory responses increase susceptibility to type 1 and type 2 diabetes. Spatiotemporal patterns of gene expression involved in immune cell polarisation depend on genomic enhancer elements in response to inflammatory and metabolic cues. Several studies have reported that most regulatory genetic variants are located in the non-protein coding regions of the genome and particularly in enhancer regions. The progress of high-throughput technologies has permitted the characterisation of enhancer chromatin properties. These advances support the concept that genetic alteration of enhancers may influence the immune and inflammatory responses in relation to diabetes. Scope of review Results from genome-wide association studies (GWAS) combined with functional and integrative analyses have elucidated the impacts of some diabetes risk-associated variants that are involved in the regulation of the immune system. Additionally, genetic variant mapping to enhancer regions may alter enhancer status, which in turn leads to aberrant expression of inflammatory genes associated with diabetes susceptibility. The focus of this review was to provide an overview of the current indications that inflammatory processes are regulated at the genetic and epigenomic levels in diabetes, along with perspectives on future research avenues that may improve understanding of the disease. Major conclusions In this review, we provide genetic evidence in support of a deregulated immune response as a risk factor in diabetes. We also argue about the importance of enhancer regions in the regulation of immune cell polarisation and how the recent advances using genome-wide methods for enhancer identification have enabled the determination of the impact of enhancer genetic variation on diabetes onset and phenotype. This could eventually lead to better management plans and improved treatment responses in human diabetes.

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Natural Genetic Variation Reveals Key Features of Epigenetic and Transcriptional Memory in Virus-Specific CD8 T Cells

Cited by 54 publications

References 82 publications

A bilateral tumor model identifies transcriptional programs associated with patient response to immune checkpoint blockade

A bilateral tumor model identifies transcriptional programs associated with patient response to immune checkpoint blockade

NK Cell Function Regulation by TGF-β-Induced Epigenetic Mechanisms

Regulation of inflammation in diabetes: From genetics to epigenomics evidence

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