scholarly journals Chromatin State and Immunotherapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. SCI-16-SCI-16
Author(s):  
W. Nicholas Haining
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Checkpoint Blockade ◽  
Chronic Viral Infection ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

Abstract The functional impairment of T cell-mediated immunity within the tumor microenvironment (TME) is a defining feature of many cancers. Checkpoint blockade therapy seeks to reinvigorate T cell responses by targeting inhibitory receptors such as PD-1, which are upregulated by dysfunctional TILs. However, the fundamental mechanisms underlying T cell dysfunction in the TME remain poorly understood, as are the mechanisms by which checkpoint blockade overcomes this dysfunction. Initial studies of dysfunctional CD8+ T cells in both human and mouse tumors suggested that they share features of T cell exhaustion, including co-inhibitory receptor upregulation and defects in cytokine production. However, more recent studies have suggested that TIL dysfunction is a unique state that is distinct from T cell exhaustion. Here we show that anti-PD-1 therapy acts on a specific subpopulation of CD8+ tumor-infiltrating lymphocytes (TILs) in melanoma mouse models as well as patients with melanoma. We find that dysfunctional CD8+ TILs possess canonical epigenetic and transcriptional features of T cell exhaustion, mirroring those seen in chronic viral infection. Similar to chronic viral infection, exhausted CD8+ TILs contain a subpopulation of "stem-like exhausted" T cells that have a distinct regulatory state. Stem-like exhausted TILs also have critical functional attributes that are not shared by the majority "terminally exhausted" TILs: they retain more polyfunctionality, persist following transfer into tumor-bearing mice, and differentiate to repopulate terminally exhausted TILs in the TME. As a result, stem-like exhausted CD8+ TILs are better able to control tumor growth than terminally exhausted cells. Stem-like exhausted, but not terminally exhausted, CD8+ TILs can respond to anti-PD-1 therapy without reversion of their exhausted epigenetic state. CD8+ T cells with a stem-like exhausted phenotype can be found in human melanoma samples and patients with a higher fraction of this subpopulation in their tumors have a significantly longer duration of response to combination checkpoint blockade therapy. Responsiveness to checkpoint blockade is therefore restricted to a subpopulation of exhausted TILs that retain specific functional properties which enable them to control tumors. Approaches to expand stem-like exhausted CD8+ T cells in the tumor microenvironment may be an important component of improving checkpoint blockade response. Disclosures Haining: Rheos Medicines: Consultancy; Iomx Therapeutics: Consultancy; Third Rock Ventures: Consultancy; Roche: Research Funding; Calico: Research Funding; Novartis: Research Funding; Tango Therapeutics: Consultancy, Equity Ownership.

scholarly journals Tissue-Specific Differences in PD-1 and PD-L1 Expression during Chronic Viral Infection: Implications for CD8 T-Cell Exhaustion

2009 ◽  
Vol 84 (4) ◽  
pp. 2078-2089 ◽  
Author(s):  
Shawn D. Blackburn ◽  
Alison Crawford ◽  
Haina Shin ◽  
Antonio Polley ◽  
Gordon J. Freeman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Therapeutic Interventions ◽  
Chronic Viral Infection ◽  
Anatomical Location ◽  
T Cell Exhaustion ◽  
Tissue Specific ◽  
Cell Exhaustion

ABSTRACT The PD-1/PD-L pathway plays a major role in regulating T-cell exhaustion during chronic viral infections in animal models, as well as in humans, and blockade of this pathway can revive exhausted CD8+ T cells. We examined the expression of PD-1 and its ligands, PD-L1 and PD-L2, in multiple tissues during the course of chronic viral infection and determined how the amount of PD-1 expressed, as well as the anatomical location, influenced the function of exhausted CD8 T cells. The amount of PD-1 on exhausted CD8 T cells from different anatomical locations did not always correlate with infectious virus but did reflect viral antigen in some tissues. Moreover, lower expression of PD-L1 in some locations, such as the bone marrow, favored the survival of PD-1Hi exhausted CD8 T cells, suggesting that some anatomical sites might provide a survival niche for subpopulations of exhausted CD8 T cells. Tissue-specific differences in the function of exhausted CD8 T cells were also observed. However, while cytokine production did not strictly correlate with the amount of PD-1 expressed by exhausted CD8 T cells from different tissues, the ability to degranulate and kill were tightly linked to PD-1 expression regardless of the anatomical location. These observations have implications for human chronic infections and for therapeutic interventions based on blockade of the PD-1 pathway.

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.

scholarly journals Tim-3 co-stimulation promotes short-term effector T cells, restricts memory precursors and is dispensable for T cell exhaustion

2017 ◽  
Author(s):  
Lyndsay Avery ◽  
Andrea L. Szymczak-Workman ◽  
Lawrence P. Kane
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
T Cell Activation ◽  
Cell Activation ◽  
Effector T Cells ◽  
Chronic Viral Infection ◽  
T Cell Exhaustion ◽  
Inhibitory Protein ◽  
Cell Exhaustion

AbstractTim-3 is highly expressed on a subset of T cells during T cell exhaustion, in settings of chronic viral infection and tumors (1, 2). Using LCMV Clone-13, a model for chronic infection, we have found that Tim-3 is neither necessary nor sufficient for the development of T cell exhaustion. Nonetheless, expression of Tim-3 was sufficient to drive resistance to PD-L1 blockade therapy during chronic infection. Strikingly, expression of Tim-3 promoted development of short-term effector T cells, at the expense of memory precursor development, after acute LCMV infection. These effects were accompanied by increased Akt/mTOR signaling in T cells expressing endogenous or ectopic Tim-3. Conversely, Akt/mTOR signaling was reduced in effector T cells from Tim-3 deficient mice. Thus, Tim-3 is essential for optimal effector T cell responses, but may also contribute to exhaustion, by restricting development of long-lived memory T cells, including PD-1int “stem-like” exhausted T cells that expand during PD-1 pathway blockade. Taken together, our results suggest that Tim-3 is actually more similar to co-stimulatory receptors that are upregulated after T cell activation, rather than a dominant inhibitory protein like PD-1. These findings have significant implications for the development of anti-Tim-3 antibodies as therapeutic agents.SignificanceDuring a chronic viral infection, prolonged exposure to viral antigens leads to dysfunction or “exhaustion” of T cells specific to the virus, a condition also observed in T cells that infiltrate tumors. The exhausted state is associated with expression of specific cell-surface proteins, some of which may inhibit T cell activation. Expression of Tim-3 is associated with acquisition of T cell exhaustion, although it is also expressed transiently during acute infection. Here we provide evidence that a major function of Tim-3 is to enhance T cell activation, during either acute or chronic viral infection. However, Tim-3 is not required for development of exhaustion. Thus, we propose that Tim-3 would be better described as a stimulatory, rather than inhibitory, protein.

T.15.5. Hyperactivation of CD8 T Cells During the Early Stages of a Persistent Viral Infection Precedes T Cell Exhaustion

2009 ◽  
Vol 131 ◽  
pp. S53-S54
Author(s):  
Kathryn Mackerness ◽  
Maureen Cox ◽  
Casey Weaver ◽  
Laurie Harrington ◽  
Allan Zajac
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Persistent Viral Infection ◽  
Early Stages

T-Cells From Patients with CLL Exhibit Phenotypic and Transcription Factor Profiles of Exhaustion Independent of CMV Serostatus

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1780-1780
Author(s):  
John C. Riches ◽  
Jeff Davies ◽  
Sameena Iqbal ◽  
Rewas Fatah ◽  
Samir Agrawal ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Dysfunction ◽  
Effector Memory ◽  
Chronic Viral Infection ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Healthy Donors

Abstract Abstract 1780 Cancer is associated with immune dysfunction, contributing to the failure to mount an effective anti-tumor immune response. T-cell exhaustion, a state of acquired T-cell dysfunction initially described in the context of chronic viral infections, has recently been described in human solid tumors. We have previously demonstrated alterations in gene expression and defects in function in T-cells from patients with chronic lymphocytic leukemia (CLL) and noted similarities to those described in exhausted T-cells in murine models. Therefore, we used multiparameter flow cytometry to determine if T-cells from patients with untreated CLL (n=23) had surface phenotypic and transcription factor profiles of exhaustion. When compared with healthy controls (n=10), an increased proportion of circulating CD8+ T-cells showed an effector-memory phenotype (p=0.018), with a shift towards a greater proportion of CCR7-CD45RA+ terminally differentiated cells. We found increased expression of markers of exhaustion including CD279 (PD-1) (p=0.0057), CD160 (p=0.0006), CD244 (p=0.0057), and CD57 (p=0.011), and decreased expression of CD28 (p=0.0058) on CLL CD8+ T-cells compared with healthy CD8+ T-cells. Increased expression of PD-1 (p=0.0019), CD160 (p=0.0011), CD57 (p=0.007), and LAG-3 (p=0.038) was also noted on CLL CD4+ T-cells. We next determined the level of the transcription factors T-bet and eomesodermin and the transcriptional repressor Blimp-1, as these proteins have been implicated in CD8+ effector-memory differentiation and development of T-cell exhaustion. Importantly, CD8+ T-cells from CLL patients showed increased expression of T-bet (p=0.038), eomesodermin (p=0.0037), and Blimp-1 (p=0.0002), compared with CD8+ T-cells from healthy donors. Furthermore, PD-1 expression identified a subset of exhausted CD8+ T-cells with high intranuclear staining of Blimp-1 that was markedly expanded in patients with CLL (p=0.0002). Previous studies have identified expanded populations of CMV specific CD8+ T-cells in CMV seropositive CLL patients. As chronic viral infection is a known cause of T-cell exhaustion, we determined whether our findings were limited to CMV seropositive patients. We observed that increased expression of T-bet and decreased expression of CD28 was seen only in CD8+ T-cells from CMV seropositive patients. T-bet represses expression of PD-1 and sustains CD8+ T-cell responses during chronic viral infection, and we noted relatively lower expression of PD-1 on CD8+ T-cells in seropositive compared with seronegative patients (p=0.049), although PD-1 expression was still higher than in healthy controls. However, CD8+ T-cells from both CMV seronegative and seropositive patients had significantly higher expression of CD160, CD244, and CD57 compared to CD8+ T-cells from healthy donors (Table 1). Furthermore, CD8+ T-cells from both CMV seronegative and seropositive patients had increased expression of Blimp-1 and eomesodermin. Table 1. Surface phenotype/transcription factor profile of CLL according to CMV serostatus Healthy CLL: CMV IgG negative (n=8) CLL: CMV IgG positive (n=8) Phenotype PD-1 LOW INCREASED** INCREASED* CD160 LOW INCREASED** INCREASED** CD57 LOW INCREASED* INCREASED** CD244 LOW INCREASED* INCREASED*** CD28 HIGH NO CHANGE DECREASED** Transcription factor T-bet LOW NO CHANGE INCREASED** Eomes LOW INCREASED* INCREASED*** Blimp-1 LOW INCREASED*** INCREASED*** * p<0.05, ** p<0.01, *** p<0.001 In conclusion, T-cells from patients with CLL show phenotypic and transcription factor profiles of T-cell exhaustion that is not limited to the CMV-seropositive group. These findings may explain the acquired immune deficiency in patients with CLL, and provide potential therapeutic targets to reverse immune dysfunction in this disease. Disclosures: Gribben: Roche: Honoraria; Celgene: Honoraria; GSK: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria; Pharmacyclics: Honoraria.

scholarly journals IL2Rβ-dependent signals drive terminal exhaustion and suppress memory development during chronic viral infection

2016 ◽  
Vol 113 (37) ◽  
pp. E5444-E5453 ◽  
Author(s):  
Jean-Christophe Beltra ◽  
Sara Bourbonnais ◽  
Nathalie Bédard ◽  
Tania Charpentier ◽  
Moana Boulangé ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Viral Infections ◽  
Adaptive Immune Response ◽  
Chronic Viral Infection ◽  
T Cell Exhaustion ◽  
Gamma Chain ◽  
Cell Exhaustion ◽  
Genetic Ablation

Exhaustion of CD8+ T cells severely impedes the adaptive immune response to chronic viral infections. Despite major advances in our understanding of the molecular regulation of exhaustion, the cytokines that directly control this process during chronicity remain unknown. We demonstrate a direct impact of IL-2 and IL-15, two common gamma-chain–dependent cytokines, on CD8+ T-cell exhaustion. Common to both cytokine receptors, the IL-2 receptor β (IL2Rβ) chain is selectively maintained on CD8+ T cells during chronic lymphocytic choriomeningitis virus and hepatitis C virus infections. Its expression correlates with exhaustion severity and identifies terminally exhausted CD8+ T cells both in mice and humans. Genetic ablation of the IL2Rβ chain on CD8+ T cells restrains inhibitory receptor induction, in particular 2B4 and Tim-3; precludes terminal differentiation of highly defective PD-1hi effectors; and rescues memory T-cell development and responsiveness to IL-7–dependent signals. Together, we ascribe a previously unexpected role to IL-2 and IL-15 as instigators of CD8+ T-cell exhaustion during chronic viral infection.

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