Down‐regulation of EOMES drives T‐cell exhaustion via abolishing EOMES‐mediated repression of inhibitory receptors of T cells in liver cancer

ABSTRACTThe hallmarks of pulmonaryMycobacterium tuberculosisinfection are lung granulomas. These organized structures are composed of host immune cells whose purpose is to contain or clear infection, creating a complex hub of immune and bacterial cell activity, as well as limiting pathology in the lungs. Yet, given cellular activity and the potential for frequent interactions between host immune cells andM. tuberculosis-infected cells, we observed a surprisingly low quantity of cytokine-producing T cells (<10% of granuloma T cells) in our recent study ofM. tuberculosisinfection within nonhuman primate (NHP) granulomas. Various mechanisms could limit T cell function, and one hypothesis is T cell exhaustion. T cell exhaustion is proposed to result from continual antigen stimulation, inducing them to enter a state characterized by low cytokine production, low proliferation, and expression of a series of inhibitory receptors, the most common being PD-1, LAG-3, and CTLA-4. In this work, we characterized the expression of inhibitory receptors on T cells and the functionality of these cells in tuberculosis (TB) lung granulomas. We then used these experimental data to calibrate and inform an agent-based computational model that captures environmental, cellular, and bacterial dynamics within granulomas in lungs duringM. tuberculosisinfection. Together, the results of the modeling and the experimental work suggest that T cell exhaustion alone is not responsible for the low quantity ofM. tuberculosis-responsive T cells observed within TB granulomas and that the lack of exhaustion is likely an intrinsic property of granuloma structure.

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Expanded antigen-experienced CD160+CD8+effector T cells exhibit impaired effector functions in chronic lymphocytic leukemia

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002189 ◽

2021 ◽

Vol 9 (4) ◽

pp. e002189

Author(s):

Najmeh Bozorgmehr ◽

Isobel Okoye ◽

Olaide Oyegbami ◽

Lai Xu ◽

Amelie Fontaine ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Effector T Cells ◽

Lymphocytic Leukemia ◽

Healthy Controls ◽

T Cell Exhaustion ◽

Inhibitory Receptors ◽

Cell Exhaustion ◽

Effector Functions ◽

Cell Effector

BackgroundT cell exhaustion compromises antitumor immunity, and a sustained elevation of co-inhibitory receptors is a hallmark of T cell exhaustion in solid tumors. Similarly, upregulation of co-inhibitory receptors has been reported in T cells in hematological cancers such as chronic lymphocytic leukemia (CLL). However, the role of CD160, a glycosylphosphatidylinositol-anchored protein, as one of these co-inhibitory receptors has been contradictory in T cell function. Therefore, we decided to elucidate how CD160 expression and/or co-expression with other co-inhibitory receptors influence T cell effector functions in patients with CLL.MethodsWe studied 56 patients with CLL and 25 age-matched and sex-matched healthy controls in this study. The expression of different co-inhibitory receptors was analyzed in T cells obtained from the peripheral blood or the bone marrow. Also, we quantified the properties of extracellular vesicles (EVs) in the plasma of patients with CLL versus healthy controls. Finally, we measured 29 different cytokines, chemokines or other biomarkers in the plasma specimens of patients with CLL and healthy controls.ResultsWe found that CD160 was the most upregulated co-inhibitory receptor in patients with CLL. Its expression was associated with an exhausted T cell phenotype. CD160+CD8+ T cells were highly antigen-experienced/effector T cells, while CD160+CD4+ T cells were more heterogeneous. In particular, we identified EVs as a source of CD160 in the plasma of patients with CLL that can be taken up by T cells. Moreover, we observed a dominantly proinflammatory cytokine profile in the plasma of patients with CLL. In particular, interleukin-16 (IL-16) was highly elevated and correlated with the advanced clinical stage (Rai). Furthermore, we observed that the incubation of T cells with IL-16 results in the upregulation of CD160.ConclusionsOur study provides a novel insight into the influence of CD160 expression/co-expression with other co-inhibitory receptors in T cell effector functions in patients with CLL. Besides, IL-16-mediated upregulation of CD160 expression in T cells highlights the importance of IL-16/CD160 as potential immunotherapy targets in patients with CLL. Therefore, our findings propose a significant role for CD160 in T cell exhaustion in patients with CLL.

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Hemophagocytic lymphohistiocytosis in syntaxin-11–deficient mice: T-cell exhaustion limits fatal disease

Blood ◽

10.1182/blood-2012-07-441139 ◽

2013 ◽

Vol 121 (4) ◽

pp. 604-613 ◽

Cited By ~ 50

Author(s):

Tamara Kögl ◽

Jürgen Müller ◽

Birthe Jessen ◽

Annette Schmitt-Graeff ◽

Gritta Janka ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

Hemophagocytic Lymphohistiocytosis ◽

Cytolytic Activity ◽

T Cell Exhaustion ◽

Inhibitory Receptors ◽

Cell Exhaustion ◽

Syntaxin 11 ◽

Deficient Mice

Abstract Syntaxin-11 (Stx11), an atypical member of the SNARE protein family, is part of the cytolytic machinery of T and NK cells and involved in the fusion of lytic granules with the plasmamembrane. Functional loss of syntaxin-11 in humans causes defective degranulation and impaired cytolytic activity of T and NK cells. Furthermore, patients with STX11 deficiency develop familial hemophagocytic lymphohistiocytosis type 4 (FHL4), a life-threatening disease of severe hyperinflammation. We established Stx11-deficient mice as an animal model for FHL4. Stx11-deficient mice exhibited severely reduced degranulation and cytolytic activity of CTL and NK cells and developed all clinical symptoms of hemophagocytic lymphohistiocytosis (HLH) after infection with lymphocytic choriomeningitis virus (LCMV). The HLH phenotype was further characterized by hyperactive CD8 T cells and continuous IFN-γ production. However, in contrast to perforin-deficient mice, which represent a model for FHL2, progression of HLH was not fatal. Survival of Stx11-deficient mice was determined by exhaustion of antigen-specific T cells, characterized by expression of inhibitory receptors, sequential loss of effector functions, and finally T-cell deletion. Blockade of inhibitory receptors on T cells in Stx11-deficient mice converted nonfatal disease course into fatal HLH, identifying T-cell exhaustion as an important factor for determination of disease severity in HLH.

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Transcriptional profiling of tumor-specific CD8 T cells shows contribution of TIGIT to T cell exhaustion in liver cancer

10.1055/s-0039-3402198 ◽

2020 ◽

Author(s):

D Ostroumov ◽

S Duong ◽

J Wingerath ◽

N Woller ◽

MP Manns ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Liver Cancer ◽

Cd8 T Cells ◽

Transcriptional Profiling ◽

T Cell Exhaustion ◽

Cell Exhaustion

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Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

Cancers ◽

10.3390/cancers12082274 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2274

Author(s):

Didem Saka ◽

Muazzez Gökalp ◽

Betül Piyade ◽

Nedim Can Cevik ◽

Elif Arik Sever ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Critical Role ◽

Single Agent ◽

T Cell Exhaustion ◽

Inhibitory Receptors ◽

Cell Exhaustion

T-cell exhaustion is a phenomenon that represents the dysfunctional state of T cells in chronic infections and cancer and is closely associated with poor prognosis in many cancers. The endogenous T-cell immunity and genetically edited cell therapies (CAR-T) failed to prevent tumor immune evasion. The effector T-cell activity is perturbed by an imbalance between inhibitory and stimulatory signals causing a reprogramming in metabolism and the high levels of multiple inhibitory receptors like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte-activation gene 3 (Lag-3). Despite the efforts to neutralize inhibitory receptors by a single agent or combinatorial immune checkpoint inhibitors to boost effector function, PDAC remains unresponsive to these therapies, suggesting that multiple molecular mechanisms play a role in stimulating the exhaustion state of tumor-infiltrating T cells. Recent studies utilizing transcriptomics, mass cytometry, and epigenomics revealed a critical role of Thymocyte selection-associated high mobility group box protein (TOX) genes and TOX-associated pathways, driving T-cell exhaustion in chronic infection and cancer. Here, we will review recently defined molecular, genetic, and cellular factors that drive T-cell exhaustion in PDAC. We will also discuss the effects of available immune checkpoint inhibitors and the latest clinical trials targeting various molecular factors mediating T-cell exhaustion in PDAC.

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Nicotinamide Inhibits T Cell Exhaustion and Increases Differentiation of CD8 Effector T Cells

Cancers ◽

10.3390/cancers14020323 ◽

2022 ◽

Vol 14 (2) ◽

pp. 323

Author(s):

Sara Alavi ◽

Abdullah Al Emran ◽

Hsin-Yi Tseng ◽

Jessamy C. Tiffen ◽

Helen Marie McGuire ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Viral Infections ◽

Effector T Cells ◽

Effector Memory ◽

T Cell Exhaustion ◽

Inhibitory Receptors ◽

Cell Exhaustion ◽

Terminal Effector

One of the limitations of immunotherapy is the development of a state referred to as T cell exhaustion (TEx) whereby T cells express inhibitory receptors (IRs) and lose production of effectors involved in killing of their targets. In the present studies we have used the repeated stimulation model with anti CD3 and anti CD28 to understand the factors involved in TEx development and treatments that may reduce changes of TEx. The results show that addition of nicotinamide (NAM) involved in energy supply to cells prevented the development of inhibitory receptors (IRs). This was particularly evident for the IRs CD39, TIM3, and to a lesser extent LAG3 and PD1 expression. NAM also prevented the inhibition of IL-2 and TNFα expression in TEx and induced differentiation of CD4+ and CD8 T cells to effector memory and terminal effector T cells. The present results showed that effects of NAM were linked to regulation of reactive oxygen species (ROS) consistent with previous studies implicating ROS in upregulation of TOX transcription factors that induce TEx. These effects of NAM in reducing changes of TEx and in increasing the differentiation of T cells to effector states appears to have important implications for the use of NAM supplements in immunotherapy against cancers and viral infections and require further exploration in vivo.

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miR-149-3p reverses CD8 + T-cell exhaustion by reducing inhibitory receptors and promoting cytokine secretion in breast cancer cells

Open Biology ◽

10.1098/rsob.190061 ◽

2019 ◽

Vol 9 (10) ◽

pp. 190061 ◽

Cited By ~ 6

Author(s):

Meng Zhang ◽

Dian Gao ◽

Yanmei Shi ◽

Yifan Wang ◽

Rakesh Joshi ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

T Cell ◽

Cancer Cells ◽

T Cell Activation ◽

Immune Escape ◽

T Cell Exhaustion ◽

Inhibitory Receptors ◽

Aberrant Expression ◽

Cell Exhaustion

Blockade of inhibitory receptors (IRs) is one of the most effective immunotherapeutic approaches to treat cancer. Dysfunction of miRNAs is a major cause of aberrant expression of IRs and contributes to the immune escape of cancer cells. How miRNAs regulate immune checkpoint proteins in breast cancer remains largely unknown. In this study, downregulation of miRNAs was observed in PD-1-overexpressing CD8 + T cells using miRNA array analysis of mouse breast cancer homografts. The data reveal that miR-149-3p was predicted to bind the 3'UTRs of mRNAs encoding T-cell inhibitor receptors PD-1, TIM-3, BTLA and Foxp1. Treatment of CD8 + T cells with an miR-149-3p mimic reduced apoptosis, attenuated changes in mRNA markers of T-cell exhaustion and downregulated mRNAs encoding PD-1, TIM-3, BTLA and Foxp1. On the other hand, T-cell proliferation and secretion of effector cytokines indicative of increased T-cell activation (IL-2, TNF-α, IFN-γ) were upregulated after miR-149-3p mimic treatment. Moreover, the treatment with a miR-149-3p mimic promoted the capacity of CD8 + T cells to kill targeted 4T1 mouse breast tumour cells. Collectively, these data show that miR-149-3p can reverse CD8 + T-cell exhaustion and reveal it to be a potential antitumour immunotherapeutic agent in breast cancer.

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Molecular Basis of T-Cell Exhaustion

Blood ◽

10.1182/blood.v122.21.sci-38.sci-38 ◽

2013 ◽

Vol 122 (21) ◽

pp. SCI-38-SCI-38

Author(s):

E. John Wherry

Keyword(s):

T Cells ◽

Transcription Factors ◽

T Cell ◽

Terminal Differentiation ◽

Cell Populations ◽

T Cell Exhaustion ◽

Inhibitory Receptors ◽

Chronic Infections ◽

Cell Exhaustion

Abstract T-cell exhaustion is common during chronic infections, cancer, exposure to persisting antigens, and can prevent optimal immunity. Exhausted T cells are defined by the loss of ability to perform effector functions efficiently, low proliferative capacity, and poor survival following antigen stimulation. In addition, it has become clear that exhausted T cells co-express multiple inhibitory receptors that negatively regulate their function. Indeed, receptors such as PD-1 have become major targets of clinical immunotherapies in cancer and infectious disease aimed at re-invigorating exhausted T cells. Our work has recently defined transcriptional networks of T-cell exhaustion and has focused on the role of key transcription factors, including T-bet and Eomesodermin (Eomes), in controlling the sustainability and terminal differentiation of exhausted T cell populations. Chronic infections and persisting antigen exposure often strains the sustainability or regenerative capacity of exhausted T cell populations resulting in an eventual collapse in immunity. We have found a key role for T-bet in sustaining a progenitor pool of exhausted CD8 T cells during chronic infection, while the related transcription factor Eomes governs terminal differentiation. These represent unique functions for T-bet and Eomes since these transcription factors are associated with different roles in functional memory T cells, highlighting the contextual dependence of transcriptional regulation guiding T-cell exhaustion. Additional studies are focusing on the role of other transcription factors such as BATF in T-cell activation and exhaustion, and on the role of inhibitory receptors including PD-1 in shaping the differentiation of exhausted CD8 T-cell subsets. Ultimately, a more precise molecular understanding of T-cell exhaustion should lead to novel and more robust clinical interventions to reverse exhaustion in settings of persisting infections and cancer. Disclosures: Wherry: Genentech: Patents & Royalties.

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