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Current Opinion in Immunology Apr 2013Human tumors progress despite the presence of tumor associated antigen (TAA)-specific T cells. Many different molecular and cellular mechanisms contribute to the failure... (Review)
Review
Human tumors progress despite the presence of tumor associated antigen (TAA)-specific T cells. Many different molecular and cellular mechanisms contribute to the failure of T cells to eradicate the tumor. These include immune suppressive networks that impair ongoing T cell function and enable tumor escape. Recent studies have started to reveal the nature of effector T cells in the tumor microenvironment. In this article we discuss T cell anergy, exhaustion, senescence, and stemness, and review the phenotype of dysfunctional T cell subsets and the underlying molecular mechanisms in the tumor microenvironments. We suggest that targeting T cell dysfunctional mechanisms and introducing/promoting T cell stemness are important approaches to treat patients with cancer.
Topics: Animals; Cellular Senescence; Clonal Anergy; Humans; Neoplasms; Stem Cells; T-Lymphocytes; Tumor Microenvironment
PubMed: 23298609
DOI: 10.1016/j.coi.2012.12.003 -
Cancer Cell Apr 2018Therapeutic reinvigoration of tumor-specific T cells has greatly improved clinical outcome in cancer. Nevertheless, many patients still do not achieve durable benefit.... (Review)
Review
Therapeutic reinvigoration of tumor-specific T cells has greatly improved clinical outcome in cancer. Nevertheless, many patients still do not achieve durable benefit. Recent evidence from studies in murine and human cancer suggest that intratumoral T cells display a broad spectrum of (dys-)functional states, shaped by the multifaceted suppressive signals that occur within the tumor microenvironment. Here we discuss the current understanding of T cell dysfunction in cancer, the value of novel technologies to dissect such dysfunction at the single cell level, and how our emerging understanding of T cell dysfunction may be utilized to develop personalized strategies to restore antitumor immunity.
Topics: Animals; Clonal Anergy; Humans; Immunotherapy; Neoplasms; Precision Medicine; T-Lymphocytes; Tumor Microenvironment
PubMed: 29634943
DOI: 10.1016/j.ccell.2018.03.012 -
Immunity Oct 2007Chronic viral infections often result in T cell exhaustion. To determine the molecular signature of exhaustion, we compared the gene-expression profiles of dysfunctional...
Chronic viral infections often result in T cell exhaustion. To determine the molecular signature of exhaustion, we compared the gene-expression profiles of dysfunctional lymphocytic choriomeningitis virus (LCMV)-specific CD8(+) T cells from chronic infection to functional LCMV-specific effector and memory CD8(+) T cells generated after acute infection. These data showed that exhausted CD8(+) T cells: (1) overexpressed several inhibitory receptors, including PD-1, (2) had major changes in T cell receptor and cytokine signaling pathways, (3) displayed altered expression of genes involved in chemotaxis, adhesion, and migration, (4) expressed a distinct set of transcription factors, and (5) had profound metabolic and bioenergetic deficiencies. T cell exhaustion was progressive, and gene-expression profiling indicated that T cell exhaustion and anergy were distinct processes. Thus, functional exhaustion is probably due to both active suppression and passive defects in signaling and metabolism. These results provide a framework for designing rational immunotherapies during chronic infections.
Topics: Animals; CD8-Positive T-Lymphocytes; Cell Differentiation; Chronic Disease; Clonal Anergy; Female; Flow Cytometry; Gene Expression; Gene Expression Profiling; Immunologic Memory; Lymphocyte Activation; Lymphocytic choriomeningitis virus; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Oligonucleotide Array Sequence Analysis; Phenotype; Virus Diseases
PubMed: 17950003
DOI: 10.1016/j.immuni.2007.09.006 -
Trends in Immunology Feb 2014CD8 T cell activation and differentiation are tightly controlled, and dependent on the context in which naïve T cells encounter antigen, can either result in functional... (Review)
Review
CD8 T cell activation and differentiation are tightly controlled, and dependent on the context in which naïve T cells encounter antigen, can either result in functional memory or T cell dysfunction, including exhaustion, tolerance, anergy, or senescence. With the identification of phenotypic and functional traits shared in different settings of T cell dysfunction, distinctions between such dysfunctional states have become blurred. Here, we discuss distinct states of CD8 T cell dysfunction, with an emphasis on: (i) T cell tolerance to self-antigens (self-tolerance); (ii) T cell exhaustion during chronic infections; and (iii) tumor-induced T cell dysfunction. We highlight recent findings on cellular and molecular characteristics defining these states, cell-intrinsic regulatory mechanisms that induce and maintain them, and strategies that can lead to their reversal.
Topics: Animals; CD8-Positive T-Lymphocytes; Cell Differentiation; Clonal Anergy; Epigenesis, Genetic; Humans; Immune Tolerance; Immunologic Memory; Infections; Lymphocyte Activation; Mice; Neoplasms; Self Tolerance
PubMed: 24210163
DOI: 10.1016/j.it.2013.10.001 -
Cellular & Molecular Immunology May 2020Bispecific antibodies (bsAbs) refer to a large family of molecules that recognize two different epitopes or antigens. Although a series of challenges, especially... (Review)
Review
Bispecific antibodies (bsAbs) refer to a large family of molecules that recognize two different epitopes or antigens. Although a series of challenges, especially immunogenicity and chain mispairing issues, once hindered the development of bsAbs, they have been gradually overcome with the help of rapidly developing technologies in the past 5 decades. In the meantime, an increasing number of bsAb platforms have been designed to satisfy different clinical demands. Currently, numerous preclinical and clinical trials are underway, portraying a promising future for bsAb-based cancer treatment. Nevertheless, bsAb drugs still face enormous challenges in their application as cancer therapeutics, including tumor heterogeneity and mutational burden, intractable tumor microenvironment (TME), insufficient costimulatory signals to activate T cells, the necessity for continuous injection, fatal systemic side effects, and off-target toxicities to adjacent normal cells. Therefore, we provide several strategies as solutions to these issues, which comprise generating multispecific bsAbs, discovering neoantigens, combining bsAbs with other anticancer therapies, exploiting natural killer (NK)-cell-based bsAbs and producing bsAbs in situ. In this review, we mainly discuss previous and current challenges in bsAb development and underscore corresponding strategies, with a brief introduction of several typical bsAb formats.
Topics: Animals; Antibodies, Bispecific; Antigens; Antineoplastic Agents; Clonal Anergy; Humans; Immunotherapy; Killer Cells, Natural
PubMed: 32313210
DOI: 10.1038/s41423-020-0417-8 -
Nature Immunology Sep 2020The majority of tumor-infiltrating T cells exhibit a terminally exhausted phenotype, marked by a loss of self-renewal capacity. How repetitive antigenic stimulation...
The majority of tumor-infiltrating T cells exhibit a terminally exhausted phenotype, marked by a loss of self-renewal capacity. How repetitive antigenic stimulation impairs T cell self-renewal remains poorly defined. Here, we show that persistent antigenic stimulation impaired ADP-coupled oxidative phosphorylation. The resultant bioenergetic compromise blocked proliferation by limiting nucleotide triphosphate synthesis. Inhibition of mitochondrial oxidative phosphorylation in activated T cells was sufficient to suppress proliferation and upregulate genes linked to T cell exhaustion. Conversely, prevention of mitochondrial oxidative stress during chronic T cell stimulation allowed sustained T cell proliferation and induced genes associated with stem-like progenitor T cells. As a result, antioxidant treatment enhanced the anti-tumor efficacy of chronically stimulated T cells. These data reveal that loss of ATP production through oxidative phosphorylation limits T cell proliferation and effector function during chronic antigenic stimulation. Furthermore, treatments that maintain redox balance promote T cell self-renewal and enhance anti-tumor immunity.
Topics: Adenosine Diphosphate; Animals; Antigens, Neoplasm; Antioxidants; CD8-Positive T-Lymphocytes; Cell Proliferation; Cell Self Renewal; Clonal Anergy; Energy Metabolism; Immune Tolerance; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mitochondria; Neoplasms; Oxidative Phosphorylation
PubMed: 32661364
DOI: 10.1038/s41590-020-0725-2 -
Immunity Feb 2015During persistent antigen stimulation, CD8(+) T cells show a gradual decrease in effector function, referred to as exhaustion, which impairs responses in the setting of...
During persistent antigen stimulation, CD8(+) T cells show a gradual decrease in effector function, referred to as exhaustion, which impairs responses in the setting of tumors and infections. Here we demonstrate that the transcription factor NFAT controls the program of T cell exhaustion. When expressed in cells, an engineered form of NFAT1 unable to interact with AP-1 transcription factors diminished T cell receptor (TCR) signaling, increased the expression of inhibitory cell surface receptors, and interfered with the ability of CD8(+) T cells to protect against Listeria infection and attenuate tumor growth in vivo. We defined the genomic regions occupied by endogenous and engineered NFAT1 in primary CD8(+) T cells and showed that genes directly induced by the engineered NFAT1 overlapped with genes expressed in exhausted CD8(+) T cells in vivo. Our data show that NFAT promotes T cell anergy and exhaustion by binding at sites that do not require cooperation with AP-1.
Topics: Animals; CD8-Positive T-Lymphocytes; Cells, Cultured; Clonal Anergy; Gene Expression Regulation; Listeria monocytogenes; Listeriosis; Lymphocyte Activation; Mice; Mice, Transgenic; NFATC Transcription Factors; Neoplasms; Promoter Regions, Genetic; Receptors, Antigen, T-Cell; Recombinant Proteins; Transcription Factor AP-1
PubMed: 25680272
DOI: 10.1016/j.immuni.2015.01.006 -
Clinical Reviews in Allergy & Immunology Oct 2018Oral tolerance is a state of systemic unresponsiveness that is the default response to food antigens in the gastrointestinal tract, although immune tolerance can also be... (Review)
Review
Oral tolerance is a state of systemic unresponsiveness that is the default response to food antigens in the gastrointestinal tract, although immune tolerance can also be induced by other routes, such as the skin or inhalation. Antigen can be acquired directly by intestinal phagocytes, or pass through enterocytes or goblet cell-associated passages prior to capture by dendritic cells (DCs) in the lamina propria. Mucin from goblet cells acts on DCs to render them more tolerogenic. A subset of regulatory DCs expressing CD103 is responsible for delivery of antigen to the draining lymph node and induction of Tregs. These DCs also imprint gastrointestinal homing capacity, allowing the recently primed Tregs to home back to the lamina propria where they interact with macrophages that produce IL-10 and expand. Tregs induced by dietary antigen include Foxp3 Tregs and Foxp3 Tregs. In addition to Tregs, T cell anergy can also contribute to oral tolerance. The microbiota plays a key role in the development of oral tolerance, through regulation of macrophages and innate lymphoid cells that contribute to the regulatory phenotype of gastrointestinal dendritic cells. Absence of microbiota is associated with a susceptibility to food allergy, while presence of Clostridia strains can suppress development of food allergy through enhancement of Tregs and intestinal barrier function. It is not clear if feeding of antigens can also induce true immune tolerance after a memory immune response has been generated, but mechanistic studies of oral immunotherapy trials demonstrate shared pathways in oral tolerance and oral immunotherapy, with a role for Tregs and anergy. An important role for IgA and IgG antibodies in development of immune tolerance is also supported by studies of oral tolerance in humans. The elucidation of key pathways in oral tolerance could identify new strategies to increase efficacy of immunotherapy treatments for food allergy.
Topics: Administration, Oral; Animals; Clonal Anergy; Dendritic Cells; Desensitization, Immunologic; Food Hypersensitivity; Forkhead Transcription Factors; Humans; Immune Tolerance; Immunity, Innate; Microbiota; T-Lymphocytes, Regulatory
PubMed: 29488131
DOI: 10.1007/s12016-018-8680-5 -
The Journal of Experimental Medicine Dec 2023T cells that encounter self-antigens after exiting the thymus avert autoimmunity through peripheral tolerance. Pathways for this include an unresponsive state known as...
T cells that encounter self-antigens after exiting the thymus avert autoimmunity through peripheral tolerance. Pathways for this include an unresponsive state known as anergy, clonal deletion, and T regulatory (Treg) cell induction. The transcription factor cues and kinetics that guide distinct peripheral tolerance outcomes remain unclear. Here, we found that anergic T cells are epigenetically primed for regulation by the non-classical AP-1 family member BATF. Tolerized BATF-deficient CD4+ T cells were resistant to anergy induction and instead underwent clonal deletion due to proapoptotic BIM (Bcl2l11) upregulation. During prolonged antigen exposure, BIM derepression resulted in fewer PD-1+ conventional T cells as well as loss of peripherally induced FOXP3+ Treg cells. Simultaneous Batf and Bcl2l11 knockdown meanwhile restored anergic T cell survival and Treg cell maintenance. The data identify the AP-1 nuclear factor BATF as a dominant driver of sustained T cell anergy and illustrate a mechanism for divergent peripheral tolerance fates.
Topics: Transcription Factor AP-1; Bcl-2-Like Protein 11; Clonal Anergy; T-Lymphocytes, Regulatory; Autoantigens
PubMed: 37862030
DOI: 10.1084/jem.20230183 -
Journal of Immunology (Baltimore, Md. :... Apr 2017Selective suppression of effector CD4 T cell functions is necessary to prevent immune cell-mediated damage to healthy tissues. This appears especially true during... (Review)
Review
Selective suppression of effector CD4 T cell functions is necessary to prevent immune cell-mediated damage to healthy tissues. This appears especially true during pregnancy or in individuals predisposed to autoimmunity. Foxp3 regulatory T (T) cells and induction of anergy, an acquired state of T cell functional unresponsiveness in Foxp3 cells, have both been implicated as mechanisms to suppress dangerous immune responses to tissue-restricted self-Ags. Anergic CD4 T cells and T cells share a number of phenotypic and mechanistic traits-including the expression of CD73 and folate receptor 4, and the epigenetic modification of T cell signature genes-and an interesting relationship between these two subsets has recently emerged. In this review, we will compare and contrast these two subsets, as well as explore the role of anergy in the generation of peripheral T cells.
Topics: Animals; Clonal Anergy; Humans; T-Lymphocytes, Regulatory
PubMed: 28320913
DOI: 10.4049/jimmunol.1602031