Cholesterol induces CD8+ T-cell exhaustion in the tumor microenvironment

2019 ◽  
Vol 110 ◽  
pp. S9-S10
Author(s):  
Q. Yi
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Cd8 T Cell ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

Abstract IA26: Breast tumor microenvironment in black women: A distinct signature of CD8+ T-cell exhaustion

2020 ◽  
Author(s):  
Song Yao ◽  
Ting-Yuan Cheng ◽  
Ahmed Elkhanany ◽  
Li Yan ◽  
Angela Omilian ◽  
...  
Keyword(s):  
Black Women ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Breast Tumor ◽  
Cd8 T Cell ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

scholarly journals Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment

2019 ◽  
Vol 30 (1) ◽  
pp. 143-156.e5 ◽  
Author(s):  
Xingzhe Ma ◽  
Enguang Bi ◽  
Yong Lu ◽  
Pan Su ◽  
Chunjian Huang ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Cd8 T Cell ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

scholarly journals Exploring Markers of Exhausted CD8 T Cells to Predict Response to Immune Checkpoint Inhibitor Therapy for Hepatocellular Carcinoma

Liver Cancer ◽  
2021 ◽  
pp. 1-14
Author(s):  
Chia-Lang Hsu ◽  
Da-Liang Ou ◽  
Li-Yuan Bai ◽  
Chia-Wei Chen ◽  
Li Lin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Cd8 T Cell ◽  
Gene Signature ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

<b><i>Background:</i></b> Reversal of CD8 T-cell exhaustion was considered a major antitumor mechanism of anti-programmed cell death-1 (PD-1)/ anti-programmed death ligand-1 (PD-L1)-based immune checkpoint inhibitor (ICI) therapy. <b><i>Objectives:</i></b> The aim of this study was to identify markers of T-cell exhaustion that is best associated with ICI treatment efficacy for advanced hepatocellular carcinoma (HCC). <b><i>Methods:</i></b> Immune cell composition of archival tumor samples was analyzed by transcriptomic analysis and multiplex immunofluorescence staining. <b><i>Results:</i></b> HCC patients with objective response after anti-PD-1/anti-PD-L1-based ICI therapy (<i>n</i> = 42) had higher expression of genes related to T-cell exhaustion. A 9-gene signature (LAG3, CD244, CCL5, CXCL9, CXCL13, MSR1, CSF3R, CYBB, and KLRK1) was defined, whose expression was higher in patients with response to ICI therapy, correlated with density of CD8<sup>+</sup>LAG3<sup>+</sup> cells in tumor microenvironment, and independently predicted better progression-free and overall survival. This 9-gene signature had similar predictive values for patients who received single-agent or combination ICI therapy and was not associated with prognosis in HCC patients who received surgery, suggesting that it may outperform other T-cell signatures for predicting efficacy of ICI therapy for HCC. For HCC patients who underwent surgery for both the primary liver and metastatic lung tumors (<i>n</i> = 31), lung metastatic HCC was associated with a higher exhausted CD8 T-cell signature, consistent with prior observation that patients with lung metastatic HCC may have higher probability of response to ICI therapy. <b><i>Conclusions:</i></b> CD8 T-cell exhaustion in tumor microenvironment may predict better efficacy of ICI therapy for HCC.

scholarly journals The Potential of T Cell Factor 1 in Sustaining CD8+ T Lymphocyte-Directed Anti-Tumor Immunity

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 515
Author(s):  
Sungmin Jung ◽  
Jea-Hyun Baek
Keyword(s):  
T Cell ◽  
Tumor Immunity ◽  
T Lymphocyte ◽  
Critical Role ◽  
Cd8 T Cell ◽  
Immune Checkpoint Blockade ◽  
Viral Escape ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
T Cell Factor

T cell factor 1 (TCF1) is a transcription factor that has been highlighted to play a critical role in the promotion of T cell proliferation and maintenance of cell stemness in the embryonic and CD8+ T cell populations. The regulatory nature of TCF1 in CD8+ T cells is of great significance, especially within the context of T cell exhaustion, which is linked to the tumor and viral escape in pathological contexts. Indeed, inhibitory signals, such as programmed cell death 1 (PD-1) and cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4), expressed on exhausted T lymphocytes (TEX), have become major therapeutic targets in immune checkpoint blockade (ICB) therapy. The significance of TCF1 in the sustenance of CTL-mediated immunity against pathogens and tumors, as well as its recently observed necessity for an effective anti-tumor immune response in ICB therapy, presents TCF1 as a potentially significant biomarker and/or therapeutic target for overcoming CD8+ T cell exhaustion and resistance to ICB therapy. In this review, we aim to outline the recent findings on the role of TCF1 in T cell development and discuss its implications in anti-tumor immunity.

scholarly journals A novel spontaneous hepatocellular carcinoma mouse model for studying T-cell exhaustion in the tumor microenvironment

2018 ◽  
Vol 6 (1) ◽  
Author(s):  
Yu-Tzu Liu ◽  
Tai-Chung Tseng ◽  
Ruey-Shyang Soong ◽  
Chun-Yi Peng ◽  
Yu-Hsing Cheng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Mouse Model ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

scholarly journals 644 Tumor-mediated suppressive signaling and hypoxia supports altered chromatin landscapes that limit the transcriptional and functional potential of terminal T cell exhaustion

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A673-A673
Author(s):  
Rhodes Ford ◽  
Natalie Rittenhouse ◽  
Nicole Scharping ◽  
Paolo Vignali ◽  
Greg Delgoffe ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Histone Modifications ◽  
Cd8 T Cells ◽  
Tumor Hypoxia ◽  
T Cell Subsets ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

BackgroundCD8+ T cells are a fundamental component of the anti-tumor response; however, tumor-infiltrating CD8+ T cells (TIL) are rendered dysfunctional by the tumor microenvironment. CD8+ TIL display an exhausted phenotype with decreased cytokine expression and increased expression of co-inhibitory receptors (IRs), such as PD-1 and Tim-3. The acquisition of IRs mark the progression of dysfunctional TIL from progenitors (PD-1Low) to terminally exhausted (PD-1+Tim-3+). How the chromatin landscape changes during this progression has not been described.MethodsUsing a low-input ChIP-based assay called Cleavage Under Targets and Release Using Nuclease (CUT&RUN), we have profiled the histone modifications at the chromatin of tumor-infiltrating CD8+ T cell subsets to better understand the relationship between the epigenome and the transcriptome as TIL progress towards terminal exhaustion.ResultsWe have identified two epigenetic characteristics unique to terminally exhausted cells. First, we have identified a unique set of genes, characterized by active histone modifications that do not have correlated gene expression. These regions are enriched for AP-1 transcription factor motifs, yet most AP-1 family factors are actively downregulated in terminally exhausted cells, suggesting signals that promote downregulation of AP-1 expression negatively impacts gene expression. We have shown that inducing expression of AP-1 factors with a 41BB agonist correlates with increased expression of these anticorrelated genes. We have also found a substantial increase in the number of genes that exhibit bivalent chromatin marks, defined by the presence of both active (H3K4me3) and repressive (H3K27me3) chromatin modifications that inhibit gene expression. These bivalent genes in terminally exhausted T cells are not associated with plasticity and represent aberrant hypermethylation in response to tumor hypoxia, which is necessary and sufficient to promote downregulation of bivalent genes.ConclusionsOur study defines for the first time the roles of costimulation and the tumor microenvironment in driving epigenetic features of terminally exhausted tumor-infiltrating T cells. These results suggest that terminally exhausted T cells have genes that are primed for expression, given the right signals and are the basis for future work that will elucidate that factors that drive progression towards terminal T cell exhaustion at the epigenetic level and identify novel therapeutic targets to restore effector function of tumor T cells and mediate tumor clearance.

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