ABSTRACT
Cancer patients often receive a combination of antibodies targeting programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen-4 (CTLA4). We conducted a window-of-opportunity study in head and neck squamous cell carcinoma (HNSCC) to examine the contribution of anti-CTLA4 to anti-PD-L1 therapy. Single-cell profiling of on- versus pre-treatment biopsies identified T cell expansion as an early response marker. In tumors, anti-PD-L1 triggered the expansion of mostly CD8+ T cells, whereas combination therapy expanded both CD4+ and CD8+ T cells. Such CD4+ T cells exhibited an activated T helper 1 (Th1) phenotype. CD4+ and CD8+ T cells co-localized with and were surrounded by dendritic cells expressing T cell homing factors or antibody-producing plasma cells. T cell receptor tracing suggests that anti-CTLA4, but not anti-PD-L1, triggers the trafficking of CD4+ naive/central-memory T cells from tumor-draining lymph nodes (tdLNs), via blood, to the tumor wherein T cells acquire a Th1 phenotype. Thus, CD4+ T cell activation and recruitment from tdLNs are hallmarks of early response to anti-PD-L1 plus anti-CTLA4 in HNSCC.
Subject(s)
CD8-Positive T-Lymphocytes , Head and Neck Neoplasms , Humans , Squamous Cell Carcinoma of Head and Neck , B7-H1 Antigen/genetics , CTLA-4 Antigen , Head and Neck Neoplasms/drug therapy , CD4-Positive T-Lymphocytes , Tumor MicroenvironmentABSTRACT
Autoimmunity arises when mechanisms of immune tolerance fail. Here we discuss mechanisms of T cell activation and tolerance and the dynamics of the autoimmune response at the site of disease. Live imaging of autoimmunity provides the ability to analyze immune cell dynamics at the single-cell level within the complex intact environment where disease occurs. These analyses have revealed mechanisms of T cell activation and tolerance in the lymph nodes, mechanisms of T cell entry into sites of autoimmune disease, and mechanisms leading to pathogenesis or protection in the autoimmune lesions. The overarching conclusions point to stable versus transient T cell antigen presenting cell interactions dictating the balance between T cell activation and tolerance, and T cell restimulation as a driver of pathogenesis at the site of autoimmunity. Findings from models of multiple sclerosis and type 1 diabetes are highlighted, however, the results have implications for basic mechanisms of T cell regulation during immune responses, tumor immunity, and autoimmunity.
Subject(s)
Autoimmunity , Diabetes Mellitus, Type 1 , Humans , Immune Tolerance , Lymphocyte Activation , T-LymphocytesABSTRACT
The recruitment of cells with effector functions into the tumor microenvironment holds potential for delaying cancer progression. We show that subsets of human CD28-effector CD8 T cells, CCR7- CD45RO+ effector memory, and CCR7- CD45RO- effector memory RA phenotypes, express the chemerin receptor CMKLR1 and bind chemerin via the receptor. CMKLR1-expressing human CD8 effector memory T cells present gene, protein, and cytotoxic features of NK cells. Active chemerin promotes chemotaxis of CMKLR1-expressing CD8 effector memory cells and triggers activation of the α4ß1 integrin. In an experimental prostate tumor mouse model, chemerin expression is downregulated in the tumor microenvironment, which is associated with few tumor-infiltrating CD8+ T cells, while forced overexpression of chemerin by mouse prostate cancer cells leads to an accumulation of intra-tumor CD8+ T cells. Furthermore, α4 integrin blockade abrogated the chemerin-dependent recruitment of CD8+ T effector memory cells into implanted prostate tumors in vivo. The results identify a role for chemerin:CMKLR1 in defining a specialized NK-like CD8 T cell, and suggest the use of chemerin-dependent modalities to target effector CMKLR1-expressing T cells to the tumor microenvironment for immunotherapeutic purposes.
Subject(s)
CD8-Positive T-Lymphocytes , Neoplasms , Humans , Animals , Mice , CD8-Positive T-Lymphocytes/metabolism , Receptors, CCR7/metabolism , T-Lymphocyte Subsets/metabolism , Killer Cells, Natural/metabolism , Neoplasms/metabolism , Chemokines/genetics , Chemokines/metabolism , Tumor Microenvironment , Intercellular Signaling Peptides and Proteins/metabolismABSTRACT
CD8+ T cells have evolved as one of the most motile mammalian cell types, designed to continuously scan peptide-major histocompatibility complexes class I on the surfaces of other cells. Chemoattractants and adhesion molecules direct CD8+ T-cell homing to and migration within secondary lymphoid organs, where these cells colocalize with antigen-presenting dendritic cells in confined tissue volumes. CD8+ T-cell activation induces a switch to infiltration of non-lymphoid tissue (NLT), which differ in their topology and biophysical properties from lymphoid tissue. Here, we provide a short overview on regulation of organism-wide trafficking patterns during naive T-cell recirculation and their switch to non-lymphoid tissue homing during activation. The migratory lifestyle of CD8+ T cells is regulated by their actomyosin cytoskeleton, which translates chemical signals from surface receptors into mechanical work. We explore how properties of the actomyosin cytoskeleton and its regulators affect CD8+ T cell function in lymphoid and non-lymphoid tissue, combining recent findings in the field of cell migration and actin network regulation with tissue anatomy. Finally, we hypothesize that under certain conditions, intrinsic regulation of actomyosin dynamics may render NLT CD8+ T-cell populations less dependent on input from extrinsic signals during tissue scanning.
Subject(s)
Actin Cytoskeleton/metabolism , Actomyosin/metabolism , CD8-Positive T-Lymphocytes/immunology , Animals , Cell Movement , Humans , Immunity, Cellular , Immunologic Surveillance , Lymphocyte Activation , Signal TransductionABSTRACT
PURPOSE: Infiltrating into the vital structure of the brain, located in the inaccessible anatomical region, and having molecular heterogeneity, glioblastoma (GBM) -with no doubt- is one of the deadliest cancers. Using the blood and brain barrier (BBB), GBM makes a shield to restrict the reach of chemotherapeutic agents to the tumor site and evolves a unique microenvironment to furnish all the essentials for cancer cells survival to conceal neoplastic cells from immunosurveillance. METHODS: 99 papers which met the criteria of eligibility were included in this review by consensus. The included articles were classified based on their design and level of evidence. RESULTS: Given this characteristic, immunotherapies for a while enjoyed unprecedented attention as a solution for GBM treatment; however, it did not take long before the enthusiasm for their application was muted. It became apparent that cancer cells intelligently find a way to manipulate the anti-tumor responses of agents by attracting immunosuppressive lymphocytes into the brain using the lymphatic vessels. This event makes GBM a good model for immunotherapy resistance. However, the presence of lymphatic vessels has fired up an idea of the adoptive attraction of effector T lymphocytes to the tumor milieu. This was when engineering and cloning technologies, which have given life to one of the recent treatment strategies using artificial T cells named chimeric antigen receptors (CAR) T-cells, came to action to design specific CAR T-cells for the treatment of GBM. CONCLUSION: The present review summarizes the recent advances in CAR T-cell-based treatments in GBM and discusses why this approach could be positioned as a pillar of the next-generation of immunotherapies for this type of brain tumor.
Subject(s)
Brain Neoplasms , Glioblastoma , Receptors, Chimeric Antigen , Brain Neoplasms/metabolism , Brain Neoplasms/therapy , Glioblastoma/metabolism , Humans , Immunotherapy, Adoptive , Receptors, Chimeric Antigen/metabolism , T-Lymphocytes/metabolism , Tumor MicroenvironmentABSTRACT
Inhibition of immune checkpoints programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on T cells results in durable antitumor activity in melanoma patients. Despite high frequency of melanoma brain metastases (BrM) and associated poor prognosis, the activity and mechanisms of immune checkpoint inhibitors (ICI) in metastatic tumors that develop within the "immune specialized" brain microenvironment, remain elusive. We established a melanoma tumor transplantation model with intracranial plus extracranial (subcutaneous) tumor, mimicking the clinically observed coexistence of metastases inside and outside the brain. Strikingly, intracranial ICI efficacy was observed only when extracranial tumor was present. Extracranial tumor was also required for ICI-induced increase in CD8+ T cells, macrophages, and microglia in brain tumors, and for up-regulation of immune-regulatory genes. Combined PD-1/CTLA-4 blockade had a superior intracranial efficacy over the two monotherapies. Cell depletion studies revealed that NK cells and CD8+ T cells were required for intracranial anti-PD-1/anti-CTLA-4 efficacy. Rather than enhancing CD8+ T cell activation and expansion within intracranial tumors, PD-1/CTLA-4 blockade dramatically (â¼14-fold) increased the trafficking of CD8+ T cells to the brain. This was mainly through the peripheral expansion of homing-competent effector CD8+ T cells and potentially further enhanced through up-regulation of T cell entry receptors intercellular adhesion molecule 1 and vascular adhesion molecule 1 on tumor vasculature. Our study indicates that extracranial activation/release of CD8+ T cells from PD-1/CTLA-4 inhibition and potentiation of their recruitment to the brain are paramount to the intracranial anti-PD-1/anti-CTLA-4 activity, suggesting augmentation of these processes as an immune therapy-enhancing strategy in metastatic brain cancer.
Subject(s)
Antibodies, Monoclonal/pharmacology , Brain Neoplasms/therapy , CD8-Positive T-Lymphocytes/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Melanoma, Experimental/therapy , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Brain Neoplasms/immunology , Brain Neoplasms/secondary , Female , Granzymes/immunology , Melanoma, Experimental/immunology , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Programmed Cell Death 1 Receptor/immunology , Skin Neoplasms/immunology , Skin Neoplasms/secondary , Skin Neoplasms/therapy , Tumor Burden , Tumor Cells, CulturedABSTRACT
Adoptive transfer of T cells gene-engineered with T cell receptors (TCRs) has proven its feasibility and therapeutic potential in the treatment of malignant tumors. To ensure further clinical development of TCR gene therapy, it is necessary to accurately select TCRs that demonstrate antigen-selective responses that are restricted to tumor cells and, at the same time, include strategies that restore or enhance the entry, migration and local accumulation of T cells in tumor tissues. Here, we present the current standing of TCR-engineered T cell therapy, discuss and propose procedures to select TCRs as well as strategies to sensitize the tumor to T cell trafficking, and provide a rationale for combination therapies with TCR-engineered T cells.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cancer Vaccines/immunology , Immunotherapy, Adoptive/methods , Neoplasms/therapy , Receptors, Antigen, T-Cell/metabolism , Recombinant Fusion Proteins/metabolism , Antigens, Neoplasm/immunology , CD8-Positive T-Lymphocytes/transplantation , Cell Movement , Genetic Therapy , Humans , Neoplasms/immunology , Receptors, Antigen, T-Cell/genetics , Recombinant Fusion Proteins/genetics , T-Cell Antigen Receptor Specificity , Tumor MicroenvironmentABSTRACT
The extracellular matrix polysaccharide hyaluronan (HA) accumulates at sites of autoimmune inflammation, including white matter lesions in multiple sclerosis (MS), but its functional importance in pathogenesis is unclear. We have evaluated the impact of 4-methylumbelliferone (4-MU), an oral inhibitor of HA synthesis, on disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Treatment with 4-MU decreases the incidence of EAE, delays its onset, and reduces the severity of established disease. 4-MU inhibits the activation of autoreactive T cells and prevents their polarization toward a Th1 phenotype. Instead, 4-MU promotes polarization toward a Th2 phenotpye and induction of Foxp3(+) regulatory T cells. Further, 4-MU hastens trafficking of T cells through secondary lymphoid organs, impairs the infiltration of T cells into the CNS parenchyma, and limits astrogliosis. Together, these data suggest that HA synthesis is necessary for disease progression in EAE and that treatment with 4-MU may be a potential therapeutic strategy in CNS autoimmunity. Considering that 4-MU is already a therapeutic, called hymecromone, that is approved to treat biliary spasm in humans, we propose that it could be repurposed to treat MS.
Subject(s)
Cell Polarity , Hyaluronic Acid/biosynthesis , Lymphocyte Activation , T-Lymphocytes/immunology , Animals , Hyaluronic Acid/antagonists & inhibitors , Hymecromone/pharmacology , Mice , Mice, Inbred C57BLABSTRACT
It is widely accepted that development of autoimmunity in the central nervous system (CNS) is triggered by autoreactive T cells, that are activated in the periphery and gain the capacity to migrate through endothelial cells at the blood-brain barrier (BBB) into the CNS. Upon local reactivation, an inflammatory cascade is initiated, that subsequently leads to a recruitment of additional immune cells ultimately causing demyelination and axonal damage. Even though the interaction of immune cells with the BBB has been in the focus of research for many years, the exact mechanisms of how immune cells enter and exit the CNS remains poorly understood. In this line, the factors deciding immune cell entry routes, lesion formation, cellular composition as well as distribution within the CNS have also not been elucidated. The following factors have been proposed to represent key determinants for lesion evaluation and distribution: (i) presence and density of (auto) antigens in the CNS, (ii) local immune milieu at sites of lesion development and resolution, (iii) trafficking routes and specific trafficking requirements, especially at the BBB and (iv) characteristics and phenotypes of CNS infiltrating cells and cell subsets (e.g. features of T helper subtypes or CD8 cells). The heterogeneity of lesion development within inflammatory demyelinating diseases remains poorly understood until today, but here especially orphan inflammatory CNS disorders such as neuromyelitis optica spectrum disorder (NMOSD), Rasmussen encephalitis or SUSAC syndrome might give important insights in critical determinants of lesion topography. Finally, investigating the interaction of T cells with the BBB using in vitro approaches or tracking of T cells in vivo in animals or even human patients, as well as the discovery of lymphatic vasculature in the CNS are teaching us new aspects during the development of CNS autoimmunity. In this review, we discuss recent findings which help to unravel mechanisms underlying lesion topography and might lead to new diagnostic or therapeutic approaches in neuroinflammatory disorders including multiple sclerosis (MS).
Subject(s)
Autoimmunity/immunology , Demyelinating Autoimmune Diseases, CNS/immunology , Demyelinating Autoimmune Diseases, CNS/pathology , Animals , Blood-Brain Barrier/physiopathology , HumansABSTRACT
Random mutations leading to loss of cell cycle control is not a rare occurrence in an organism but the mutated cells are recognized and eliminated preventing the development of a tumor. These potentially tumorigenic cells release damage-associated molecular patterns (DAMPs), which are recognized by toll-like receptors (TLRs) on macrophages and dendritic cells. The initial TLR-DAMP interactions lead to different responses such as altered antigen presentation and cytokine release that directly affect T cell activation and removal of the tumorigenic cells. The indirect effects of TLR-DAMP interaction include chemokine-directed altered T cell trafficking, angiogenesis for both T cell infiltration and tumor cell metastasis, and alteration of intra-tumoral milieu contributing to the development of tumor cells heterogeneity. Thus, the initial TLR-DAMP interaction has a set of local effects that modulate tumor cell growth and heterogeneity and a disseminating set of central effects that dynamically affect T cell trafficking and functions. Herein, we argue that the DAMP-TLR-cytokine axis in the tumor microenvironment serves as the mainstay that orchestrates and regulates the pro- and anti-tumor elements which dynamically interact between themselves eventuating in tumor regression or growth. The knowledge of this TLR-based immuno-surveillance framework is a key to developing a novel immunotherapy against cancer.
Subject(s)
Cytokines/metabolism , Neoplasms/metabolism , Pathogen-Associated Molecular Pattern Molecules/metabolism , Signal Transduction , Toll-Like Receptors/metabolism , Animals , Humans , Neoplasms/immunology , Neoplasms/pathology , Tumor MicroenvironmentABSTRACT
Within the tumor microenvironment, IL-6 signaling is generally considered a malevolent player, assuming a dark visage that promotes tumor progression. Chronic IL-6 signaling is linked to tumorigenesis in numerous mouse models as well as in human disease. IL-6 acts intrinsically on tumor cells through numerous downstream mediators to support cancer cell proliferation, survival, and metastatic dissemination. Moreover, IL-6 can act extrinsically on other cells within the complex tumor microenvironment to sustain a pro-tumor milieu by supporting angiogenesis and tumor evasion of immune surveillance. A lesser known role for IL-6 signaling has recently emerged in which it plays a beneficial role, presenting a fairer face that opposes tumor growth by mobilizing anti-tumor T cell immune responses to attain tumor control. Accumulating evidence establishes IL-6 as a key player in the activation, proliferation and survival of lymphocytes during active immune responses. IL-6 signaling can also resculpt the T cell immune response, shifting it from a suppressive to a responsive state that can effectively act against tumors. Finally, IL-6 plays an indispensable role in boosting T cell trafficking to lymph nodes and to tumor sites, where they have the opportunity to become activated and execute their cytotoxic effector functions, respectively. Here, we discuss the dual faces of IL-6 signaling in the tumor microenvironment; the dark face that drives malignancy, and the fairer aspect that promotes anti-tumor adaptive immunity.
Subject(s)
Interleukin-6/metabolism , Neoplasms/metabolism , Tumor Microenvironment , Adaptive Immunity , Animals , Cell Movement/genetics , Cell Movement/immunology , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/immunology , Cell Transformation, Neoplastic/metabolism , Cellular Microenvironment/genetics , Cellular Microenvironment/immunology , Humans , Interleukin-6/genetics , Lymph Nodes/immunology , Lymph Nodes/metabolism , Neoplasms/genetics , Neoplasms/immunology , Signal Transduction , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Tumor Microenvironment/genetics , Tumor Microenvironment/immunologyABSTRACT
Current clinical success with anti-cancer immunotherapy provides exciting new treatment opportunities. While encouraging, more needs to be done to induce durable effects in a higher proportion of patients. Increasing anti-tumor effector T cell quantity or quality alone does not necessarily correlate with therapeutic outcome. Instead, the tumor microenvironment is a critical determinant of anti-cancer responsiveness to immunotherapy and can confer profound resistance. Yet, the tumor-promoting environment - due to its enormous plasticity - also delivers the best opportunities for adjuvant therapy aiming at recruiting, priming and sustaining anti-tumor cytotoxicity. While the tumor environment as an entity is increasingly well understood, current interventions are still broad and often systemic. In contrast, tumors grow in a highly compartmentalized environment which includes the vascular/perivascular niche, extracellular matrix components and in some tumors lymph node aggregates; all of these structures harbor and instruct subsets of immune cells. Targeting and re-programming specific compartments may provide better opportunities for adjuvant immunotherapy.
Subject(s)
Neoplasms/immunology , Animals , Extracellular Matrix/physiology , Humans , Immunotherapy , Neoplasms/blood supply , Neoplasms/therapy , T-Lymphocytes/immunology , Tumor MicroenvironmentABSTRACT
Given that donor T cells from a transplant contribute both the desired graft-versus-tumour (GVT) effect and detrimental graft-versus-host disease (GVHD), strategies to separate GVHD and GVT activity are a major clinical goal. We have previously demonstrated that in vivo administration of a recombinant (r)IL-7/HGFß hybrid cytokine, consisting of interleukin-7 (IL-7, IL7) and the ß-chain of hepatocyte growth factor (HGFß), significantly inhibits the growth of cancer cells in murine tumour models. The antit-umour effect of rIL-7/HGFß is related to a marked infiltration T cells in the tumour tissues. We have also shown that GVHD was not induced in rIL-7/HGFß-treated T cell-depleted allogeneic haematopoietic stem cell transplantation (HSCT) recipients. We show here that, in T cell-replete allogeneic HSCT murine models, rIL-7/HGFß attenuated acute GVHD (aGVHD), while promoting GVT activity. This was related to an alteration of donor T cell trafficking, with an increased infiltration of donor T cells into tumour tissues and the lympho-haematopoietic system but decreased number of the T cells in the GVHD target organs. Therefore, rIL-7/HGFß may offer a new tool to alleviate aGVHD while prompting GVT, and to study the molecular regulation of T cell trafficking.
Subject(s)
Chemotaxis/drug effects , Graft vs Host Disease/immunology , Graft vs Tumor Effect/drug effects , Hepatocyte Growth Factor/pharmacology , Interleukin-7/pharmacology , Recombinant Fusion Proteins/pharmacology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Tissue Donors , Animals , Cell Line, Tumor , Chemokines/metabolism , Chemotaxis/immunology , Cytokines/metabolism , Disease Models, Animal , Graft vs Host Disease/drug therapy , Graft vs Host Disease/mortality , Graft vs Tumor Effect/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Hepatocyte Growth Factor/genetics , Interleukin-7/genetics , Mice , Neoplasms/complications , Neoplasms/immunology , Neoplasms/pathology , Neoplasms/therapy , Recombinant Fusion Proteins/genetics , T-Lymphocytes/metabolism , Tumor Burden/drug effectsABSTRACT
Recent results have identified critical components of the T cell response involved in the initiation and amplification phases of psoriasis. However the link between T cell responses arising in the skin and the systemic inflammation associated with severe psoriasis is largely unknown. We hypothesized that specific subsets of memory T cells recirculating from the skin could play a role. We therefore dissected the circulating memory T cell compartment in patients by analyzing the TCM, TEM and Teff phenotype, the pattern of CCR4 and CCR5 chemokine receptor expression and the expression of the tissue homing molecule CD103. For each subset we calculated the correlation with the Psoriasis Area and Severity Index (PASI) and with the extent of systemic inflammation measured as serum level of the prototypic short pentraxin, C reactive protein (CRP). Validation was performed by comparison with gene expression data in psoriatic plaques. We found that circulating CD103(+)CCR4(+)CCR5(+) and CCR4(+)CCR6(-) CD8(+) Teff cells, were highly correlated with CRP levels as well as with the validated index PASI, reflecting a link between skin involvement and systemic inflammation in patients with severe psoriasis. In addition we observed a contraction of circulating CCR5(+) T cells in psoriasis patients, with a highly significant inverse correlation between CCR5(+)CD4 T cells and the PASI score. Increased expression of CCR5 and CCL5 genes in psoriatic skin lesions was consistent with an accumulation of CCR5(+) cells in psoriatic plaques indicating a role for CCR5/CCL5 axis in disease pathogenesis.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Phenotype , Psoriasis/etiology , Psoriasis/metabolism , T-Lymphocyte Subsets/immunology , Adult , Antigens, CD/metabolism , Biomarkers , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Case-Control Studies , Cell Movement , Cluster Analysis , Combined Modality Therapy , Cytokines/blood , Cytokines/metabolism , Female , Gene Expression Profiling , Humans , Immunologic Memory , Inflammation/complications , Integrin alpha Chains/metabolism , Lymphocyte Count , Male , Middle Aged , Psoriasis/complications , Psoriasis/diagnosis , Receptors, CCR4/metabolism , Receptors, CCR5/genetics , Receptors, CCR5/metabolism , Severity of Illness Index , T-Lymphocyte Subsets/metabolismABSTRACT
The variable response to therapy in multiple sclerosis (MS) suggests a need for personalized approaches based on individual genetic differences. GWAS have linked CBLB gene polymorphisms with MS and recent evidence demonstrated that these polymorphisms can be associated with abnormalities in T cell function and response to interferon-ß therapy. Cbl-b is an E3 ubiquitin ligase that regulates T cell activation and Cbl-b-deficient (Cbl-b(-/-)) mice show T cell abnormalities described in MS patients. We now show that Cbl-b(-/-) T cells demonstrate significant lymph node trafficking abnormalities. We thus asked whether the MS-approved drug, FTY720, postulated to trap T cells in lymphoid tissues, is less effective in the context of Cbl-b dysfunction. We now report that FTY720 significantly inhibits EAE in Cbl-b(-/-) mice. Our results newly document a role for Cbl-b in T cell trafficking but suggest nevertheless that MS patients with Cbl-b abnormalities may still be excellent candidates for FTY720 treatment.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Cell Movement/genetics , Encephalomyelitis, Autoimmune, Experimental/immunology , Immunosuppressive Agents/pharmacology , Lymph Nodes/metabolism , Multiple Sclerosis/immunology , Propylene Glycols/pharmacology , Proto-Oncogene Proteins c-cbl/genetics , Sphingosine/analogs & derivatives , T-Lymphocytes/metabolism , Adaptor Proteins, Signal Transducing/immunology , Adoptive Transfer , Animals , Cell Movement/drug effects , Cell Movement/immunology , Fingolimod Hydrochloride , Homeodomain Proteins/genetics , Immunosuppressive Agents/therapeutic use , Lymph Nodes/drug effects , Lymph Nodes/immunology , Lymphocyte Activation/drug effects , Lymphocyte Activation/genetics , Mice , Mice, Knockout , Multiple Sclerosis/drug therapy , Propylene Glycols/therapeutic use , Proto-Oncogene Proteins c-cbl/immunology , Sphingosine/pharmacology , Sphingosine/therapeutic use , T-Lymphocytes/drug effectsABSTRACT
AIMS: AMG 181 pharmacokinetics/pharmacodynamics (PK/PD), safety, tolerability and effects after single subcutaneous (s.c.) or intravenous (i.v.) administration were evaluated in a randomized, double-blind, placebo-controlled study. METHODS: Healthy male subjects (n= 68) received a single dose of AMG 181 or placebo at 0.7, 2.1, 7, 21, 70 mg s.c. (or i.v.), 210 mg s.c. (or i.v.), 420 mg i.v. or placebo. Four ulcerative colitis (UC) subjects (n= 4, male : female 2:2) received 210 mg AMG 181 or placebo s.c. (3:1). AMG 181 concentration, anti-AMG 181-antibody (ADA), α4 ß7 receptor occupancy (RO), target cell counts, serum C-reactive protein, fecal biomarkers and Mayo score were measured. Subjects were followed 3-9 months after dose. RESULTS: Following s.c. dosing, AMG 181 was absorbed with a median tmax ranging between 2-10 days and a bioavailability between 82% and 99%. Cmax and AUC increased dose-proportionally and approximately dose-proportionally, respectively, within the 70-210 mg s.c. and 70-420 mg i.v. ranges. The linear ß-phase t1/2 was 31 (range 20-48) days. Target-mediated disposition occurred at serum AMG 181 concentrations of less than 1 µg ml(-1) . The PD effect on α4 ß7 RO showed an EC50 of 0.01 µg ml(-1) . Lymphocytes, eosinophils, CD4+ T cells and subset counts were unchanged. AMG 181-treated UC subjects were in remission with mucosal healing at weeks 6, 12 and/or 28. The placebo-treated UC subject experienced colitis flare at week 6. No ADA or AMG 181 treatment-related serious adverse events were observed. CONCLUSIONS: AMG 181 has PK/PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Inflammatory Bowel Diseases/drug therapy , Adult , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal, Humanized , CD4-Positive T-Lymphocytes/drug effects , Double-Blind Method , Female , Humans , MaleABSTRACT
Humanized mouse models have, over the past few years, seen dramatic improvements, including the colonization of both lymphoid and nonlymphoid tissues with all major immune cell lineages, the development of T cells with human major histocompatibility complex restriction, and the ability to mount functional adaptive immune responses to human pathogens, as documented in some instances. This has greatly increased the range of questions related to the biology of human immunodeficiency virus (HIV) infection that can be usefully addressed through experimental approaches utilizing small animal models. Among these approaches is in vivo imaging, and specifically multiphoton intravital microscopy (MP-IVM), which allows for the investigation of dynamic biological processes at cellular and subcellular resolution in the tissues of live animals. We have recently begun to use MP-IVM in lymph nodes of humanized mice in order to examine HIV infectious spread in vivo at the tissue and cellular level. Here, we provide a short perspective on the close link between the patterns of immune cell migration and the mechanisms of viral dissemination, and summarize the results of our initial studies.
Subject(s)
Disease Models, Animal , HIV Infections/immunology , HIV Infections/pathology , Microscopy/methods , Optical Imaging/methods , Animals , Humans , Lymph Nodes/immunology , Lymph Nodes/pathology , Mice , Mice, SCIDABSTRACT
Lymphatic endothelial cells (LECs) of the lymph node (LN) parenchyma orchestrate leukocyte trafficking and peripheral T cell dynamics. T cell responses to immunotherapy largely rely on peripheral T cell recruitment in tumors. Yet, a systematic and molecular understanding of how LECs within the LNs control T cell dynamics under steady-state and tumor-bearing conditions is lacking. Intravital imaging combined with immune phenotyping shows that LEC-specific deletion of the essential autophagy gene Atg5 alters intranodal positioning of lymphocytes and accrues their persistence in the LNs by increasing the availability of the main egress signal sphingosine-1-phosphate. Single-cell RNA sequencing of tumor-draining LNs shows that loss of ATG5 remodels niche-specific LEC phenotypes involved in molecular pathways regulating lymphocyte trafficking and LEC-T cell interactions. Functionally, loss of LEC autophagy prevents recruitment of tumor-infiltrating T and natural killer cells and abrogates response to immunotherapy. Thus, an LEC-autophagy program boosts immune-checkpoint responses by guiding systemic T cell dynamics.
Subject(s)
Autophagy , Immune Checkpoint Inhibitors , Lymph Nodes , Sphingosine/analogs & derivatives , T-Lymphocytes , Autophagy/drug effects , Animals , Lymph Nodes/immunology , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Mice , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Mice, Inbred C57BL , Autophagy-Related Protein 5/metabolism , Autophagy-Related Protein 5/genetics , Endothelial Cells/metabolism , Sphingosine/pharmacology , Sphingosine/metabolism , Humans , Lysophospholipids/metabolism , Immunotherapy/methods , Cell MovementABSTRACT
Targeting leukocyte trafficking in the management of inflammatory bowel disease [IBD] has been a significant therapeutic advance over the past 15 years. However, as with other advanced therapies, phase III clinical trials report response to trafficking inhibitors in only a proportion of patients, with fewer achieving clinical remission or mucosal healing. Additionally, there have been significant side effects, most notably progressive multifocal leukoencephalopathy in association with the α4 inhibitor natalizumab. This article reviews the mechanisms underpinning T cell recruitment and residence, to provide a background from which the strength and limitations of agents that disrupt leukocyte trafficking can be further explored. The therapeutic impact of trafficking inhibitors is underpinned by the complexity and plasticity of the intestinal immune response. Pathways essential for gut homing in health may be bypassed in the inflamed gut, thus providing alternative routes of entry when conventional homing molecules are targeted. Furthermore, there is conservation of trafficking architecture between proinflammatory and regulatory T cells. The persistence of resident memory cells within the gut gives rise to local established pro-inflammatory populations, uninfluenced by inhibition of trafficking. Finally, trafficking inhibitors may give rise to effects beyond the intended response, such as the impact of vedolizumab on innate immunity, as well as on target side effects. With significant research efforts into predictive biomarkers already underway, it is ultimately hoped that a better understanding of trafficking and residence will help us predict which patients are most likely to respond to inhibition of leukocyte trafficking, and how best to combine therapies.
Subject(s)
Inflammatory Bowel Diseases , Humans , Inflammatory Bowel Diseases/therapy , Intestines , Natalizumab/therapeutic use , Leukocytes , Immunity, InnateABSTRACT
Effective anti-cancer immune responses require activation of one or more naïve T cells. If the correct naïve T cell encounters its cognate antigen presented by an antigen presenting cell, then the T cell can activate and proliferate. Here, mathematical modeling is used to explore the possibility that immune activation in lymph nodes is a rate-limiting step in anti-cancer immunity and can affect response rates to immune checkpoint therapy. The model provides a mechanistic framework for optimizing cancer immunotherapy and developing testable solutions to unleash anti-tumor immune responses for more patients with cancer. The results show that antigen production rate and trafficking of naïve T cells into the lymph nodes are key parameters and that treatments designed to enhance tumor antigen production can improve immune checkpoint therapies. The model underscores the potential of radiation therapy in augmenting tumor immunogenicity and neoantigen production for improved ICB therapy, while emphasizing the need for careful consideration in cases where antigen levels are already sufficient to avoid compromising the immune response.