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 518 Epigenetic dysfunction of terminally exhausted tumor infiltrating T cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A554-A554
Author(s):  
Rhodes Ford ◽  
Paolo Vignali ◽  
Natalie Rittenhouse ◽  
Nicole Scharping ◽  
Andrew Frisch ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
Regulation Of Gene Expression ◽  
Tumor Hypoxia ◽  
T Cell Subsets ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Drive Gene

BackgroundTumor-infiltrating CD8+ T cells have been characterized by their exhausted phenotype with decreased cytokine expression and increased expression of co-inhibitory receptors, such as PD-1 and Tim-3. These receptors mark the progression towards exhaustion from a progenitor stage (PD-1Low) to a terminally exhausted stage (PD-1+Tim-3+). While the epigenetics of tumor-infiltrating T cells are unique compared to naïve, effector, and memory populations, 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 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 found a substantial increase in the number of genes that exhibit bivalent chromatin marks, defined by the presence of both activating (H3K4me3) and repressive (H3K27me3) epigenetic modifications that inhibit gene expression. In contrast to stem cells which exhibit bivalency, bivalent genes in terminally exhausted T cells are not associated with plasticity and represent aberrant hypermethylation in response to tumor hypoxia. Secondly, we have also identified a unique set of enhancers, characterized by H3K27ac that do not drive gene expression. These enhancers are enriched for AP-1 transcription factors, whereas enhancers that correlate with gene transcription are enriched for nuclear receptor (NR) transcription factors. Intriguingly, while most AP-1 and NR transcription factors are not expressed in terminally exhausted cells, we found that Batf, an inhibitory AP-1 family member, and Nr4a2, a NR known to promote both exhaustion and modify chromatin were specifically expressed in terminally exhausted cells. These data suggest the balance of Batf and Nr4a2 may modulate the enhancer landscape to promote terminal exhaustion, while hypoxia simultaneously promotes hypermethylation and gene repression.ConclusionsOur study defines for the first time the features of epigenetic dysfunction in tumor-mediated T cell exhaustion and deepens our understanding of the epigenetic regulation of gene expression. These observations are the bases 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.

PD-1+ T Cell Subsets in Follicular Lymphoma Tumor Microenvironment and Their Implications for Prognosis and Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2648-2648
Author(s):  
Fuliang Chu ◽  
Wencai Ma ◽  
Tomohide Yamazaki ◽  
Myriam Foglietta ◽  
Durga Nattama ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Follicular Lymphoma ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
T Cell Subsets ◽  
Prognostic Impact ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

Abstract Abstract 2648 Background: Programmed death (PD)-1, a coinhibitory receptor expressed by effector T cells (Teffs) is highly expressed on intratumoral T cells (mean 61%, range 34–86% for CD4+ T cells and mean 44%, range 31–69% for CD8+ T cells) in follicular lymphoma (FL), a finding associated with impaired ability to recognize autologous tumor (Nattamai et al, ASH 2007). Hence, PD-1 expression would be expected to confer an unfavorable prognosis in FL. However, correlation of PD-1 with clinical outcome in FL has been inconsistent with two studies showing favorable (Carreras et al, J Clin Oncol 2009; Wahlin et al, Clin Cancer Res 2010) and one study showing unfavorable (Richendollar et al, Hum Pathol 2011) outcome. While differences in method of analysis and type of treatment may explain the disparate results, a more complex model may be necessary to understand the prognostic impact of PD-1 in FL as PD-1 is expressed not only on antitumor Teffs but also on protumor follicular helper T cells (Tfh) and regulatory T cells (Tregs). Methods: To determine the nature of PD-1+ T cells in FL we performed comprehensive genomic and immunologic studies. By flow cytometry, we observed that the intratumoral CD4+ T cells in FL may be categorized into 3 subsets based on PD-1 expression - PD-1 high (PD-1hi), intermediate (PD-1int), and low (PD-1lo). The intratumoral CD8+ T cells consisted of PD-1int and PD-1lo subsets. The 3 CD4+ T cell subsets were FACSorted from FL tumors (n=3) and whole genome gene expression profiling (GEP) was performed. T cell subsets sorted similarly from tonsils served as controls for reactive follicular hyperplasia (FH) (n=3). Differentially expressed genes in GEP studies were confirmed at the mRNA level by real-time PCR (n=5) and at the protein level by flow cytometry when antibodies were available (n=5–10). Results: Our results suggested that CD4+PD-1hi T cells are Tfh cells (CXCR5hiBcl6hi ICOShiCD40LhiSAPhiPRDM1loIL-4hiIL-21hi); the CD4+PD-1int T cells consisted of a mixture of activated Teffs (CD45RO+CD45RA−) including Th1 (Tbet+IFNg+), Th2 (IL-10+), and Th17 cells (RORc+IL-17+), and Tregs (Foxp3+CD25hiCD127lo); and the CD4+PD-1lo T cells consisted of a mixture of activated Teffs (CD45RO+CD45RA− but IFNg−IL-4−IL-10−IL-17−), Tregs, and naïve T cells (CD45RO−CD45RA+CCR7+). Although these subsets were present in both FL and FH, there were important differences. IL-4 expression was significantly higher in Tfh in FL vs. FH and may play a role in the pathogenesis of FL. IL-17 expression was low and expression of coinhibitory molecules BTLA and CD200 was high in CD4+PD-1int T cells in FL vs. FH. BTLA and CD200 were also increased in CD8+PD-1int T cells in FL vs. FH. However, other coinhibitory molecules (LAG-3, Tim-3, CD160, CTLA-4, CD244, KLRG1) were not significantly different between FL and FH. CD4+PD-1int T cells also had higher expression of BATF, a transcription factor associated with T cell exhaustion in FL vs. FH. Together, these results suggest that the CD4+PD-1int T cells in FL may be in a state of T cell exhaustion whereas the CD4+PD-1int T cells in FH may represent recently activated Teffs. Consistent with this, blocking PD-1 with anti-PD-1 blocking antibody significantly enhanced proliferation and the production of Th1 (IFNg, TNFa) but not Th2 (IL-4, IL-5, IL-10, IL-13) cytokines by intratumoral CD4+ and CD8+ T cells in response to stimulation with autologous FL tumor cells (n=3). As expected, Tregs were increased in number in FL vs. FH and were present in the PD-1int and PD-1lo T cell subsets. We found 74% (range 40–97%) of FL Tregs expressed PD-1. Among the CD4+PD-1lo and CD8+PD-1lo T cells, there were more activated Teffs and fewer naïve T cells in FL vs. FH. Conclusions: Our results suggest that the PD-1+ T cells in FL are comprised of a mixture of antitumor Teffs and protumor Tfh and Tregs. The prognostic impact of PD-1+ T cells in FL may dependent on the relative frequency of these subsets as ligation of PD-1 may produce favorable (inhibition of protumor Tfh and Tregs) or unfavorable (inhibition of antitumor Teffs) outcomes by inhibiting or promoting tumor growth, respectively. Conversely, our results imply that agents that block PD-1/PD-ligand pathway may have the opposite effect on these T cell subsets and enumeration of the intratumoral PD-1+ T cell subsets may serve as biomarker to predict response to these agents in FL and possibly other B-cell malignancies. Disclosures: Dong: GSK: Consultancy; Genentech: Honoraria; Tempero: Consultancy; Ono: Consultancy; AnaptysBio: Consultancy. Neelapu:Cure Tech Ltd: Research Funding.

Integrative Genomic Analysis of HIV-Specific CD8+ T Cells Reveals That PD-1 Inhibits T Cell Function by Upregulating the AP-1 Transcription Factor BATF.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 916-916
Author(s):  
Michael Quigley ◽  
Florencia Pereyra ◽  
Bjorn Nilsson ◽  
Quentin Eichbaum ◽  
Boris Julg ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Mouse Model ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Genomic Analysis ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
T Cell Function

Abstract Abstract 916 T cells responding to chronic infections such as HIV lose the ability to secrete cytokines or to proliferate, functions critical for control of viral replication, in a process termed exhaustion. However the molecular mechanisms of T cell exhaustion are not understood, and few therapeutic targets to reinvigorate exhausted T cells have been identified. We therefore conducted a comprehensive genomic analysis of HIV-specific CD8+ T cells to identify the mechanisms underlying defective function in T cell exhaustion. We used Affymetrix microarrays to study gene expression profiles from sorted Gag-specific tetramer+ CD8+ T cells in two cohorts of HIV-infected individuals that differed in their extent of T cell exhaustion: a) Progressors (n=24), who show chronic elevation of viral load and have defects in HIV-specific T cell cytokine secretion, proliferation and survival; and b) Controllers (n=18), who show spontaneous control of viral replication and have relatively good HIV-specific T cell function. Profiles of Gag-specific CD8+ T cells (median 21,500 cells/sample) from progressors showed marked alterations in gene expression compared with those from controllers (n=518 genes upregulated in progressors, moderated t-statistic >2.0). There was highly significant similarity at the whole-genome level between dysfunctional Gag-specific CD8+ T cells from progressors and exhausted CD8+ T cells in the mouse model of chronic LCMV infection (gene set enrichment analysis, P=4.8e−005), suggesting that T cell exhaustion is associated with an evolutionarily conserved program of gene expression. Next, we determined whether this exhausted signature was influenced by inhibitory signaling via the receptor PD-1, an inhibitory receptor known to be upregulated in expression on exhausted T cells. We developed an in vitro model of PD-1 signaling and identified a unique signature of genes upregulated by PD-1 ligation. The signature of PD-1 induced genes was highly significantly upregulated in profiles from Gag-specific CD8+ T cells in HIV progressors compared to controllers (P=5e−006), and in exhausted CD8+ T cells from the LCMV mouse model (P=2e−004). Thus the signature of T cell exhaustion in humans and mice is driven in part by the consequences of PD-1 signaling. Finally, we asked whether the genes upregulated by PD-1 in exhausted T cells directly inhibit T cell function. PD-1 ligation upregulated the transcription factor BATF in HIV-specific CD8+ T cells and in exhausted CD8+ T cells from the mouse model of LCMV infection. Enforced expression of BATF, an inhibitory member of the AP-1 family, in normal human T cells inhibited proliferation (P=0.02) and IL2 secretion (P=4.5e-05). Infection with LCMV in BATF transgenic mice resulted in marked acceleration of T cell exhaustion compared to wild-type animals, indicating that BATF represses T cell effector functions. Silencing of BATF using shRNA in primary human T cells showed that it was required for PD-1 mediated inhibition of T cell function. In summary, our results demonstrate that 1) PD-1 ligation induces a conserved transcriptional program in exhausted HIV-specific CD8+ T cells and in exhausted LCMV-specific CD8+ T cells in the mouse; 2) this transcriptional program includes the upregulation of genes such as BATF that directly inhibit T cell function. Our data suggest that BATF causes the functional defects seen in T cell exhaustion, and represents a new therapeutic target to rescue T cell function in HIV infection. Disclosures: No relevant conflicts of interest to declare.

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.

549 Characterizing double positive T cells in the tumor microenvironment: a tale of promiscuous cell fates

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A586-A586
Author(s):  
Sara Schad ◽  
Andrew Chow ◽  
Heng Pan ◽  
Levi Mangarin ◽  
Roberta Zappasodi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Human Melanoma ◽  
B16 Melanoma ◽  
T Cell Subsets ◽  
Double Positive ◽  
Cell Fates ◽  
Single Positive

BackgroundCD4 and CD8 T cells are genetically and functionally distinct cell subsets of the adaptive immune system that play pivotal roles in immune surveillance and disease control. During development in the thymus, transcription factors ThPOK and Runx3 regulate the differentiation and maturation of these two lineages into single positive T cells that enter the periphery with mutually exclusive expression of either the CD4 or CD8 co-receptor.1–2 Despite our expectation that these two cell fates are fixed, mature CD4+CD8+ double positive (DP) T cells have been described in the context of numerous immunological responses, including cancer, but their molecular and functional properties and therapeutic relevance remain controversial and largely unknown.3–5MethodsOur lab has identified and characterized a heterogenous DP T cell population in murine and human melanoma tumors comprised of CD4 and CD8 T cells re-expressing the opposite co-receptor and a parallel uptake in the opposite cell type’s phenotype and function. Using CD4 (Trp1) and CD8 (Pmel) transgenic TCR T cells specific to B16 melanoma antigens gp75 and gp100 respectively, we demonstrate the re-expression of the opposite co-receptor following adoptive T cell transfer in B16 melanoma tumor bearing mice.ResultsSpecifically, up to 50% of transferred CD4 Trp1 T cells will re-express CD8 to become a DP T cell in the tumor microenvironment. Further, these CD4 derived DP T cells upregulate CD8 lineage regulator Runx3 and cytolytic genes Gzmb, Gzmk, and Prf1 to become potent cytotoxic T cells. Alternatively, a subset of CD8 Pmel T cells differentiate into DP T cells characterized by the increased expression of CD4, ThPOK, and regulatory marker FoxP3 (figure 1). In addition, we utilized 10x single cell and ATAC sequencing to further characterize these divergent DP T cell populations among open repertoire T cells isolated from murine and human melanoma tumors.ConclusionsOur findings highlight the capability of single positive T cells to differentiate in response to antigen and local stimuli into novel T cell subsets with polyfunctional characteristics. The resulting cell subsets will potentially affect the tumor microenvironment in distinct ways. Our studies may inform therapeutic approaches to identify antigen specific T cells as well as innovative signaling pathways to target when genetically engineering T cells to optimize cytotoxic function in the setting of adoptive cell therapy.Ethics ApprovalThe human biospecimen analyses were approved by Memorial Sloan Kettering Cancer Center IRB #06-107ReferencesEllmeier W, Haust L & Tschismarov R. Transcriptional control of CD4 and CD8 coreceptor expression during T cell development. Cell Mol Life Sci 2013;70:4537–4553.Luckey MA, et al. The transcription factor ThPOK suppresses Runx3 and imposes CD4+ lineage fate by inducing the SOCS suppressors of cytokine signaling. Nature Immunology 2014; 15, 638–645.Bohner P, et al. Double positive CD4(+)CD8(+) T Cells are enriched in urological cancers and favor T Helper-2 polarization. Front Immunol 2019; 10, 622.Nascimbeni M, Shin E-C, Chiriboga L, Kleiner DE & Rehermann B. Peripheral CD4(+)CD8(+) T cells are differentiated effector memory cells with antiviral functions. Blood 2004;104:478–486.Nishida K, et al. Clinical importance of the expression of CD4+CD8+ T cells in renal cell carcinoma. Int Immunol 2020;32:347–357.

scholarly journals Partial restoration of immune response in Hepatitis C patients after viral clearance by direct-acting antiviral therapy

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0254243
Author(s):  
Meritxell Llorens-Revull ◽  
Maria Isabel Costafreda ◽  
Angie Rico ◽  
Mercedes Guerrero-Murillo ◽  
Maria Eugenia Soria ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Hepatitis C ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Clearance ◽  
Cd4 T Cell ◽  
Care Hospital ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

Background & aims HCV CD4+ and CD8+ specific T cells responses are functionally impaired during chronic hepatitis C infection. DAAs therapies eradicate HCV infection in more than 95% of treated patients. However, the impact of HCV elimination on immune responses remain controversial. Here, we aimed to investigate whether HCV cure by DAAs could reverse the impaired immune response to HCV. Methods We analyzed 27 chronic HCV infected patients undergoing DAA treatment in tertiary care hospital, and we determined the phenotypical and functional changes in both HCV CD8+ and CD4+ specific T-cells before and after viral clearance. PD-1, TIM-3 and LAG-3 cell-surface expression was assessed by flow cytometry to determine CD4+ T cell exhaustion. Functional responses to HCV were analyzed by IFN-Ɣ ELISPOT, intracellular cytokine staining (IL-2 and IFN-Ɣ) and CFSE-based proliferation assays. Results We observed a significant decrease in the expression of PD-1 in CD4+ T-cells after 12 weeks of viral clearance in non-cirrhotic patients (p = 0.033) and in treatment-naive patients (p = 0.010), indicating a partial CD4 phenotype restoration. IFN-Ɣ and IL-2 cytokines production by HCV-specific CD4+ and CD8+ T cells remained impaired upon HCV eradication. Finally, a significant increase of the proliferation capacity of both HCV CD4+ and CD8+ specific T-cells was observed after HCV elimination by DAAs therapies. Conclusions Our results show that in chronically infected patients HCV elimination by DAA treatment lead to partial reversion of CD4+ T cell exhaustion. Moreover, proliferative capacity of HCV-specific CD4+ and CD8+ T cells is recovered after DAA’s therapies.

scholarly journals Single-Cell Transcriptome Analysis Reveals RGS1 as a New Marker and Promoting Factor for T-Cell Exhaustion in Multiple Cancers

2021 ◽  
Vol 12 ◽  
Author(s):  
Yunmeng Bai ◽  
Meiling Hu ◽  
Zixi Chen ◽  
Jinfen Wei ◽  
Hongli Du
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Poor Prognosis ◽  
Effector T Cells ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Transcriptome ◽  
Cancer Tissues ◽  
Single Cell Transcriptome

T-cell exhaustion is one of the main reasons of tumor immune escape. Using single-cell transcriptome data of CD8+ T cells in multiple cancers, we identified different cell types, in which Pre_exhaust and exhausted T cells participated in negative regulation of immune system process. By analyzing the coexpression network patterns and differentially expressed genes of Pre_exhaust, exhausted, and effector T cells, we identified 35 genes related to T-cell exhaustion, whose high GSVA scores were associated with significantly poor prognosis in various cancers. In the differentially expressed genes, RGS1 showed the greatest fold change in Pre_exhaust and exhausted cells of three cancers compared with effector T cells, and high expression of RGS1 was also associated with poor prognosis in various cancers. Additionally, RGS1 protein was upregulated significantly in tumor tissues in the immunohistochemistry verification. Furthermore, RGS1 displayed positive correlation with the 35 genes, especially highly correlated with PDCD1, CTLA4, HAVCR2, and TNFRSF9 in CD8+ T cells and cancer tissues, indicating the important roles of RGS1 in CD8+ T-cell exhaustion. Considering the GTP-hydrolysis activity of RGS1 and significantly high mRNA and protein expression in cancer tissues, we speculated that RGS1 potentially mediate the T-cell retention to lead to the persistent antigen stimulation, resulting in T-cell exhaustion. In conclusion, our findings suggest that RGS1 is a new marker and promoting factor for CD8+ T-cell exhaustion and provide theoretical basis for research and immunotherapy of exhausted cells.

scholarly journals Unraveling the Multifaceted Nature of CD8 T Cell Exhaustion Provides the Molecular Basis for Therapeutic T Cell Reconstitution in Chronic Hepatitis B and C

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2563
Author(s):  
Valeria Barili ◽  
Andrea Vecchi ◽  
Marzia Rossi ◽  
Ilaria Montali ◽  
Camilla Tiezzi ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
T Cell ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Cd8 T Cells ◽  
Stress Responses ◽  
T Cell Exhaustion ◽  
Virus Infections ◽  
Cell Exhaustion

In chronic hepatitis B and C virus infections persistently elevated antigen levels drive CD8+ T cells toward a peculiar differentiation state known as T cell exhaustion, which poses crucial constraints to antiviral immunity. Available evidence indicates that T cell exhaustion is associated with a series of metabolic and signaling deregulations and with a very peculiar epigenetic status which all together lead to reduced effector functions. A clear mechanistic network explaining how intracellular metabolic derangements, transcriptional and signaling alterations so far described are interconnected in a comprehensive and unified view of the T cell exhaustion differentiation profile is still lacking. Addressing this issue is of key importance for the development of innovative strategies to boost host immunity in order to achieve viral clearance. This review will discuss the current knowledge in HBV and HCV infections, addressing how innate immunity, metabolic derangements, extensive stress responses and altered epigenetic programs may be targeted to restore functionality and responsiveness of virus-specific CD8 T cells in the context of chronic virus infections.

PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4671-4678 ◽  
Author(s):  
Ji-Yuan Zhang ◽  
Zheng Zhang ◽  
Xicheng Wang ◽  
Jun-Liang Fu ◽  
Jinxia Yao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Effector Memory ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Specific Memory ◽  
Memory Cd8 T Cell

Abstract The immunoreceptor PD-1 is significantly up-regulated on exhausted CD8+ T cells during chronic viral infections such as HIV-1. However, it remains unknown whether PD-1 expression on CD8+ T cells differs between typical progressors (TPs) and long-term nonprogressors (LTNPs). In this report, we examined PD-1 expression on HIV-specific CD8+ T cells from 63 adults with chronic HIV infection. We found that LTNPs exhibited functional HIV-specific memory CD8+ T cells with markedly lower PD-1 expression. TPs, in contrast, showed significantly up-regulated PD-1 expression that was closely correlated with a reduction in CD4 T-cell number and an elevation in plasma viral load. Importantly, PD-1 up-regulation was also associated with reduced perforin and IFN-γ production, as well as decreased HIV-specific effector memory CD8+ T-cell proliferation in TPs but not LTNPs. Blocking PD-1/PD-L1 interactions efficiently restored HIV-specific CD8+ T-cell effector function and proliferation. Taken together, these findings confirm the hypothesis that high PD-1 up-regulation mediates HIV-specific CD8+ T-cell exhaustion. Blocking the PD-1/PD-L1 pathway may represent a new therapeutic option for this disease and provide more insight into immune pathogenesis in LTNPs.

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.

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