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Immunity Mar 2018Expression of programmed death-ligand 1 (PD-L1) is frequently observed in human cancers. Binding of PD-L1 to its receptor PD-1 on activated T cells inhibits anti-tumor... (Review)
Review
Expression of programmed death-ligand 1 (PD-L1) is frequently observed in human cancers. Binding of PD-L1 to its receptor PD-1 on activated T cells inhibits anti-tumor immunity by counteracting T cell-activating signals. Antibody-based PD-1-PD-L1 inhibitors can induce durable tumor remissions in patients with diverse advanced cancers, and thus expression of PD-L1 on tumor cells and other cells in the tumor microenviroment is of major clinical relevance. Here we review the roles of the PD-1-PD-L1 axis in cancer, focusing on recent findings on the mechanisms that regulate PD-L1 expression at the transcriptional, posttranscriptional, and protein level. We place this knowledge in the context of observations in the clinic and discuss how it may inform the design of more precise and effective cancer immune checkpoint therapies.
Topics: Animals; B7-H1 Antigen; Gene Expression Regulation; Humans; Immunotherapy; Lymphocyte Activation; Molecular Targeted Therapy; Neoplasms; Programmed Cell Death 1 Receptor; Signal Transduction; T-Lymphocytes
PubMed: 29562194
DOI: 10.1016/j.immuni.2018.03.014 -
Molecular Cancer Nov 2019The emergence of immune checkpoint inhibitors (ICIs), mainly including anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and... (Review)
Review
The emergence of immune checkpoint inhibitors (ICIs), mainly including anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies (mAbs), has shaped therapeutic landscape of some type of cancers. Despite some ICIs have manifested compelling clinical effectiveness in certain tumor types, the majority of patients still showed de novo or adaptive resistance. At present, the overall efficiency of immune checkpoint therapy remains unsatisfactory. Exploring additional immune checkpoint molecules is a hot research topic. Recent studies have identified several new immune checkpoint targets, like lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), and so on. The investigations about these molecules have generated promising results in preclinical studies and/or clinical trials. In this review, we discussed the structure and expression of these newly-characterized immune checkpoints molecules, presented the current progress and understanding of them. Moreover, we summarized the clinical data pertinent to these recent immune checkpoint molecules as well as their application prospects.
Topics: Animals; Antineoplastic Agents, Immunological; Biomarkers, Tumor; CTLA-4 Antigen; Clinical Trials as Topic; Humans; Immunomodulation; Lymphocyte Activation; Molecular Targeted Therapy; Neoplasms; Programmed Cell Death 1 Receptor; T-Lymphocytes; Treatment Outcome
PubMed: 31690319
DOI: 10.1186/s12943-019-1091-2 -
International Journal of Molecular... Oct 2020T cells follow a triphasic distinct pathway of activation, proliferation and differentiation before becoming functionally and phenotypically "exhausted" in settings of... (Review)
Review
T cells follow a triphasic distinct pathway of activation, proliferation and differentiation before becoming functionally and phenotypically "exhausted" in settings of chronic infection, autoimmunity and in cancer. Exhausted T cells progressively lose canonical effector functions, exhibit altered transcriptional networks and epigenetic signatures and gain constitutive expression of a broad coinhibitory receptor suite. This review outlines recent advances in our understanding of exhausted T cell biology and examines cellular and molecular mechanisms by which a state of dysfunction or exhaustion is established, and mechanisms by which exhausted T cells may still contribute to pathogen or tumour control. Further, this review describes our understanding of exhausted T cell heterogeneity and outlines the mechanisms by which checkpoint blockade differentially engages exhausted T cell subsets to overcome exhaustion and recover T cell function.
Topics: CD8-Positive T-Lymphocytes; Cell Differentiation; Humans; Immune Checkpoint Inhibitors; Lymphocyte Activation; Neoplasms; T-Lymphocyte Subsets
PubMed: 33027962
DOI: 10.3390/ijms21197357 -
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 -
Frontiers in Immunology 2020Not only do Adipocytes have energy storage and endocrine functions, but they also play an immunological role. Adipocytes are involved in adaptive immunity to mediate the... (Review)
Review
Not only do Adipocytes have energy storage and endocrine functions, but they also play an immunological role. Adipocytes are involved in adaptive immunity to mediate the pathological processes of a variety of chronic inflammatory diseases and autoimmune syndromes. The adaptive immune response consists of T cell-mediated cellular immunity and B cell-mediated humoral immunity. Obese adipocytes overexpress MHC class II molecules and costimulators to act as antigen-presenting cells (APCs) and promote the activation of CD4 T cells. In addition, various adipokines secreted by adipocytes regulate the proliferation and differentiation of T cells. Adipokines are also involved in B cell generation, development, activation, and antibody production. Therefore, adipocytes play an important role in B cell-mediated adaptive immunity. This review describes how adipocytes participate in adaptive immunity from the perspective of T cells and B cells, and discusses their role in the pathogenesis of various diseases.
Topics: Adaptive Immunity; Adipocytes; Adipokines; Animals; Antigen Presentation; Antigen-Presenting Cells; B-Lymphocytes; Biomarkers; Energy Metabolism; Humans; Immunomodulation; Lymphocyte Activation; T-Lymphocytes
PubMed: 33329579
DOI: 10.3389/fimmu.2020.593058 -
Science Translational Medicine Jul 2019Immunotherapy with chimeric antigen receptor (CAR)-engineered T cells can be effective against advanced malignancies. CAR T cells are "living drugs" that require...
Immunotherapy with chimeric antigen receptor (CAR)-engineered T cells can be effective against advanced malignancies. CAR T cells are "living drugs" that require technologies to enable physicians (and patients) to maintain control over the infused cell product. Here, we demonstrate that the tyrosine kinase inhibitor dasatinib interferes with the lymphocyte-specific protein tyrosine kinase (LCK) and thereby inhibits phosphorylation of CD3ζ and ζ-chain of T cell receptor-associated protein kinase 70 kDa (ZAP70), ablating signaling in CAR constructs containing either CD28_CD3ζ or 4-1BB_CD3ζ activation modules. As a consequence, dasatinib induces a function-off state in CD8 and CD4 CAR T cells that is of immediate onset and can be sustained for several days without affecting T cell viability. We show that treatment with dasatinib halts cytolytic activity, cytokine production, and proliferation of CAR T cells in vitro and in vivo. The dose of dasatinib can be titrated to achieve partial or complete inhibition of CAR T cell function. Upon discontinuation of dasatinib, the inhibitory effect is rapidly and completely reversed, and CAR T cells resume their antitumor function. The favorable pharmacodynamic attributes of dasatinib can be exploited to steer the activity of CAR T cells in "function-on-off-on" sequences in real time. In a mouse model of cytokine release syndrome (CRS), we demonstrated that a short treatment course of dasatinib, administered early after CAR T cell infusion, protects a proportion of mice from otherwise fatal CRS. Our data introduce dasatinib as a broadly applicable pharmacologic on/off switch for CAR T cells.
Topics: Animals; Cytokine Release Syndrome; Dasatinib; Dexamethasone; Female; Humans; Lymphocyte Activation; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Mice, SCID; Phosphorylation; Protein Kinase Inhibitors; Receptors, Antigen, T-Cell; T-Lymphocytes
PubMed: 31270272
DOI: 10.1126/scitranslmed.aau5907 -
Blood May 2007A characteristic feature of tumors is high production of lactic acid due to enhanced glycolysis. Here, we show a positive correlation between lactate serum levels and... (Clinical Trial)
Clinical Trial
A characteristic feature of tumors is high production of lactic acid due to enhanced glycolysis. Here, we show a positive correlation between lactate serum levels and tumor burden in cancer patients and examine the influence of lactic acid on immune functions in vitro. Lactic acid suppressed the proliferation and cytokine production of human cytotoxic T lymphocytes (CTLs) up to 95% and led to a 50% decrease in cytotoxic activity. A 24-hour recovery period in lactic acid-free medium restored CTL function. CTLs infiltrating lactic acid-producing multicellular tumor spheroids showed a reduced cytokine production. Pretreatment of tumor spheroids with an inhibitor of lactic acid production prevented this effect. Activated T cells themselves use glycolysis and rely on the efficient secretion of lactic acid, as its intracellular accumulation disturbs their metabolism. Export by monocarboxylate transporter-1 (MCT-1) depends on a gradient between cytoplasmic and extracellular lactic acid concentrations and consequently, blockade of MCT-1 resulted in impaired CTL function. We conclude that high lactic acid concentrations in the tumor environment block lactic acid export in T cells, thereby disturbing their metabolism and function. These findings suggest that targeting this metabolic pathway in tumors is a promising strategy to enhance tumor immunogenicity.
Topics: Biological Transport; Cell Cycle Proteins; Cell Proliferation; Dose-Response Relationship, Drug; Female; Glycolysis; Humans; Lactic Acid; Lymphocyte Activation; Male; Neoplasms; Oncogene Proteins; Spheroids, Cellular; T-Lymphocytes; Tumor Cells, Cultured
PubMed: 17255361
DOI: 10.1182/blood-2006-07-035972 -
RNA Biology May 2021B cells constitute a main branch adaptive immune system. They mediate host defence through the production of high-affinity antibodies against an enormous diversity of... (Review)
Review
B cells constitute a main branch adaptive immune system. They mediate host defence through the production of high-affinity antibodies against an enormous diversity of foreign antigens. Remarkably, B cells undergo multiple types of somatic DNA mutation to achieve this effector function, including class switch recombination (CSR) and somatic hypermutation (SHM). These processes occur in response to antigen recognition and inflammatory signals, and require strict biological control at multiple levels. Transcription within the locus that encodes antibodies plays direct roles in CSR. Additional non-coding RNAs (ncRNAs), including both microRNAs (miRNAs) and long ncRNAs (lncRNAs), also play pivotal roles in B cell activation and terminal effector function through post-transcriptional gene regulation and chromatin remodelling, respectively.
Topics: Adaptive Immunity; Animals; B-Lymphocytes; Gene Expression Regulation; Humans; Immunoglobulin Class Switching; Lymphocyte Activation; RNA, Untranslated
PubMed: 33586605
DOI: 10.1080/15476286.2021.1885876 -
Frontiers in Immunology 2019Reactivation of cytotoxic CD8 T-cell responses has set a new direction for cancer immunotherapy. Neutralizing antibodies targeting immune checkpoint programmed cell... (Review)
Review
Reactivation of cytotoxic CD8 T-cell responses has set a new direction for cancer immunotherapy. Neutralizing antibodies targeting immune checkpoint programmed cell death protein 1 (PD-1) or its ligand (PD-L1) have been particularly successful for tumor types with limited therapeutic options such as melanoma and lung cancer. However, reactivation of T cells is only one step toward tumor elimination, and a substantial fraction of patients fails to respond to these therapies. In this context, combination therapies targeting more than one of the steps of the cancer-immune cycle may provide significant benefits. To find the best combinations, it is of upmost importance to understand the interplay between cancer cells and all the components of the immune response. This review focuses on the elements of the complement system that come into play in the cancer-immunity cycle. The complement system, an essential part of innate immunity, has emerged as a major regulator of cancer immunity. Complement effectors such as C1q, anaphylatoxins C3a and C5a, and their receptors C3aR and C5aR1, have been associated with tolerogenic cell death and inhibition of antitumor T-cell responses through the recruitment and/or activation of immunosuppressive cell subpopulations such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), or M2 tumor-associated macrophages (TAMs). Evidence is provided to support the idea that complement blocks many of the effector routes associated with the cancer-immunity cycle, providing the rationale for new therapeutic combinations aimed to enhance the antitumor efficacy of anti-PD-1/PD-L1 checkpoint inhibitors.
Topics: Animals; Antineoplastic Agents, Immunological; Biomarkers, Tumor; Complement System Proteins; Disease Susceptibility; Humans; Immunity; Immunomodulation; Lymphocyte Activation; Neoplasms; T-Lymphocytes
PubMed: 31031765
DOI: 10.3389/fimmu.2019.00774 -
Blood Oct 2022
Topics: B-Lymphocytes; Clone Cells; Lymphocyte Activation
PubMed: 36227751
DOI: 10.1182/blood.2022017339