ABSTRACT
The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that has wide-ranging roles, including regulation of inflammation and homeostasis. AhR is not a cell surface receptor; rather, it exists in a cytoplasmic complex that responds to a wide variety of structurally dissimilar endogenous, microbial, and environmental ligands. The ubiquitous expression of AhR, its ability to be activated by a wide range of ligands, and its capacity to act as a master regulator for gene expression and homeostasis make it a promising new therapeutic target. Clinical trials of tapinarof cream have now validated AhR agonism as a therapeutic approach that can deliver significant efficacy for treating inflammatory skin diseases, including psoriasis and atopic dermatitis. Tapinarof 1% cream is a first-in-class, nonsteroidal, topical, AhR agonist with a pharmacokinetic profile that results in localized exposure at sites of disease, avoiding systemic safety concerns, drug interactions, or off-target effects. Psoriasis and atopic dermatitis both involve epidermal inflammation, cellular immune responses, dysregulation of skin barrier protein expression, and oxidative stress. On the basis of the clinical effectiveness of tapinarof cream for treating inflammatory skin diseases, we review how targeting AhR may offer a significant opportunity in other conditions that share key aspects of pathogenesis, including asthma, inflammatory bowel disease, eosinophilic esophagitis, ophthalmic, and nervous system diseases.
Subject(s)
Dermatitis, Atopic , Psoriasis , Receptors, Aryl Hydrocarbon , Receptors, Aryl Hydrocarbon/agonists , Receptors, Aryl Hydrocarbon/metabolism , Receptors, Aryl Hydrocarbon/genetics , Humans , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/immunology , Dermatitis, Atopic/genetics , Psoriasis/drug therapy , Psoriasis/immunology , Animals , Resorcinols , StilbenesABSTRACT
In addition to serving as the main physical barrier with the outside world, human skin is abundantly infiltrated with resident αß T cells that respond differently to self, infectious, microbiome, and noxious stimuli. To study skin T cells during infection and inflammation, experimental biologists track T-cell surface phenotypes and effector functions, which are often interpreted with the untested assumption that MHC proteins and peptide antigens drive measured responses. However, a broader perspective is that CD1 proteins also activate human T cells, and in skin, Langerhans cells (LCs) are abundant antigen presenting cells that express extremely high levels of CD1a. The emergence of new experimental tools, including CD1a tetramers carrying endogenous lipids, now show that CD1a-reactive T cells comprise a large population of resident T cells in human skin. Here, we review studies showing that skin-derived αß T cells directly recognize CD1a proteins, and certain bound lipids, such as contact dermatitis allergens, trigger T-cell responses. Other natural skin lipids inhibit CD1a-mediated T-cell responses, providing an entry point for the development of therapeutic lipids that block T-cell responses. Increasing evidence points to a distinct role of CD1a in type 2 and 22 T-cell responses, providing new insights into psoriasis, contact dermatitis, and other T-cell-mediated skin diseases.
Subject(s)
Dermatitis, Contact , Skin Diseases , Humans , T-Lymphocytes , Skin , Lipids , Antigens, CD1/metabolismABSTRACT
Face transplantation is a life-changing procedure for patients with severe composite facial defects. However, it is hampered by high acute rejection rates due to the immunogenicity of skin allograft and toxicity linked to high doses of immunosuppression. To reduce immunosuppression-associated complications, we, for the first time in face transplant recipients, used low-dose interleukin 2 (IL-2) therapy to expand regulatory T cells (Tregs) in vivo and to enhance immune modulation, under close immunological monitoring of peripheral blood and skin allograft. Low-dose IL-2 achieved a sustained expansion (â¼4-fold to 5-fold) of circulating Tregs and a reduction (â¼3.5-fold) of B cells. Post-IL-2 Tregs exhibited greater suppressive function, characterized by higher expression of TIM-3 and LAG3co-inhibitory molecules. In the skin allograft, Tregs increased after low-dose IL-2 therapy. IL-2 induced a distinct molecular signature in the allograft with reduced cytotoxicity-associated genes (granzyme B and perforin). Two complications were observed during the trial: one rejection event and an episode of autoimmune hemolytic anemia. In summary, this initial experience demonstrated that low-dose IL-2 therapy was not only able to promote immune regulation in face transplant recipients but also highlighted challenges related to its narrow therapeutic window. More specific targeted Treg expansion strategies are needed to translate this approach to the clinic.
Subject(s)
Facial Transplantation , Interleukin-2 , Humans , Graft Rejection , Interleukin-2/administration & dosage , Interleukin-2/immunology , Pilot Projects , T-Lymphocytes, RegulatoryABSTRACT
Tissue-resident memory T (TRM) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens. However, the biological pathways that enable the long-term survival of TRM cells are obscure. Here we show that mouse CD8+ TRM cells generated by viral infection of the skin differentially express high levels of several molecules that mediate lipid uptake and intracellular transport, including fatty-acid-binding proteins 4 and 5 (FABP4 and FABP5). We further show that T-cell-specific deficiency of Fabp4 and Fabp5 (Fabp4/Fabp5) impairs exogenous free fatty acid (FFA) uptake by CD8+ TRM cells and greatly reduces their long-term survival in vivo, while having no effect on the survival of central memory T (TCM) cells in lymph nodes. In vitro, CD8+ TRM cells, but not CD8+ TCM cells, demonstrated increased mitochondrial oxidative metabolism in the presence of exogenous FFAs; this increase was not seen in Fabp4/Fabp5 double-knockout CD8+ TRM cells. The persistence of CD8+ TRM cells in the skin was strongly diminished by inhibition of mitochondrial FFA ß-oxidation in vivo. Moreover, skin CD8+ TRM cells that lacked Fabp4/Fabp5 were less effective at protecting mice from cutaneous viral infection, and lung Fabp4/Fabp5 double-knockout CD8+ TRM cells generated by skin vaccinia virus (VACV) infection were less effective at protecting mice from a lethal pulmonary challenge with VACV. Consistent with the mouse data, increased FABP4 and FABP5 expression and enhanced extracellular FFA uptake were also demonstrated in human CD8+ TRM cells in normal and psoriatic skin. These results suggest that FABP4 and FABP5 have a critical role in the maintenance, longevity and function of CD8+ TRM cells, and suggest that CD8+ TRM cells use exogenous FFAs and their oxidative metabolism to persist in tissue and to mediate protective immunity.
Subject(s)
CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/metabolism , Fatty Acids, Nonesterified/metabolism , Immunologic Memory/immunology , Lipid Metabolism , Animals , Biological Transport , CD8-Positive T-Lymphocytes/immunology , Cell Survival , Fatty Acid-Binding Proteins/deficiency , Fatty Acid-Binding Proteins/metabolism , Female , Humans , Mice , Neoplasm Proteins/deficiency , Neoplasm Proteins/metabolism , Oxidation-Reduction , Psoriasis , Skin/cytology , Skin/immunology , Skin/virology , Vaccinia/immunology , Vaccinia/prevention & control , Vaccinia virus/immunologyABSTRACT
CD1 activates T cells, but the function and size of the possible human T cell repertoires that recognize each of the CD1 antigen-presenting molecules remain unknown. Using an experimental system that bypasses major histocompatibility complex (MHC) restriction and the requirement for defined antigens, we show that polyclonal T cells responded at higher rates to cells expressing CD1a than to those expressing CD1b, CD1c or CD1d. Unlike the repertoire of invariant natural killer T (NKT) cells, the CD1a-autoreactive repertoire contained diverse T cell antigen receptors (TCRs). Functionally, many CD1a-autoreactive T cells homed to skin, where they produced interleukin 22 (IL-22) in response to CD1a on Langerhans cells. The strong and frequent responses among genetically diverse donors define CD1a-autoreactive cells as a normal part of the human T cell repertoire and CD1a as a target of the T(H)22 subset of helper T cells.
Subject(s)
Antigens, CD1/immunology , Autoimmunity/immunology , Receptors, Antigen, T-Cell, alpha-beta/immunology , Skin/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Helper-Inducer/immunology , Cell Separation , Chemotaxis, Leukocyte/immunology , Enzyme-Linked Immunospot Assay , Flow Cytometry , Humans , Interleukins/immunology , Interleukins/metabolism , Langerhans Cells/immunology , Langerhans Cells/metabolism , Lymphocyte Activation/immunology , Reverse Transcriptase Polymerase Chain Reaction , Skin/cytology , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Helper-Inducer/cytology , T-Lymphocytes, Helper-Inducer/metabolism , Interleukin-22ABSTRACT
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with refractory cutaneous T-cell lymphoma (CTCL) through replacement of the bone marrow responsible for lymphoma cells and possibly induction of a graft-versus-lymphoma effect. However, allo-HSCT is not always curative; relapse of CTCL occurs in about half of patients post-transplant. Treatment of relapsed CTCL after allo-HSCT is challenging because post-transplant patients are at high risk of graft-versus-host disease, and this condition may be precipitated or exacerbated by standard CTCL therapies. The benefit of each potential therapy must therefore be weighed against its risk of graft versus host disease (GVHD). In this article, we review the management of relapsed CTCL after allo-HSCT. We begin with an exemplative patient whose relapsed Sezary syndrome was successfully treated without development of GVHD. We also report high-throughput T-cell receptor sequencing data obtained during the patient's disease relapse and remission. We then review general guidelines for management of relapsed CTCL and summarize all reported cases and outcomes of relapsed CTCL after transplant. We conclude by reviewing the current CTCL therapies and their risk of GVHD.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Lymphoma, T-Cell , Mycosis Fungoides , Skin Neoplasms , Graft vs Host Disease/etiology , Graft vs Host Disease/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Lymphoma, T-Cell/pathology , Mycosis Fungoides/etiology , Neoplasm Recurrence, Local/therapy , Skin Neoplasms/complications , Skin Neoplasms/therapy , Transplantation, Homologous/adverse effectsABSTRACT
PURPOSE: Resection of pediatric posterior thoracic tumors (PTTs) can be complicated by Artery of Adamkiewicz (AKA) injury. Post-op spinal ischemia occurs in approx. 3.2% of patients, typically due to iatrogenic vascular injury. Pre-op angiography (PSA) may help to avoid this complication. Herein, we aim to evaluate outcomes after initiation of routine PSA prior to PTT resection. METHODS: A single-institution retrospective review identified 25 children (< 18 years) treated for PTTs from 2009 to 2021. PTTs included: posterior mediastinum, paraspinal thorax and posterior chest wall tumors. PSA patients were compared to those without pre-operative angiography (NA). Demographics, perioperative and long-term outcomes and event-free survival (EFS) were assessed. RESULTS: Prior to 2012, eleven patients were treated without PSA. However, the last developed post-operative paraplegia secondary to spinal ischemia. Since this event, PSA has become routine for all PTTs (n = 14) identifying six AKAs and nine accessory spinal arteries. Resection was performed in ten (90.1%) NA patients and eight (57.1%) PSA patients. Based on PSA findings, resection was not offered to six patients and planned partial resection was performed in three patients. Five PSA patients required radiation therapy for local control vs two NA patients. There were no differences in recurrence or overall EFS. CONCLUSION: PSA aids in identifying patients with high-risk thoracic vascular anatomy and may prevent risk of post-operative paraplegia associated with PTT resection.
Subject(s)
Angiography , Thoracic Neoplasms , Child , Humans , Ischemia , Paraplegia/etiology , Paraplegia/prevention & control , Retrospective Studies , Thoracic Neoplasms/diagnostic imaging , Thoracic Neoplasms/surgeryABSTRACT
BACKGROUND: Natural killer T (NKT) cells are unconventional T cells that bridge innate and adaptive immunity. NKT cells have been implicated in the development of atopic dermatitis (AD). OBJECTIVE: We aimed to investigate the role of NKT cells in AD development, especially in skin. METHODS: Global proteomic and transcriptomic analyses were performed by using skin and blood from human healthy-controls and patients with AD. Levels of CXCR4 and CXCL12 expression in skin NKT cells were analyzed in human AD and mouse AD models. By using parabiosis and intravital imaging, the role of skin CXCR4+ NKT cells was further evaluated in models of mice with AD by using CXCR4-conditionally deficient or CXCL12 transgenic mice. RESULTS: CXCR4 and its cognate ligand CXCL12 were significantly upregulated in the skin of humans with AD by global transcriptomic and proteomic analyses. CXCR4+ NKT cells were enriched in AD skin, and their levels were consistently elevated in our models of mice with AD. Allergen-induced NKT cells participate in cutaneous allergic inflammation. Similar to tissue-resident memory T cells, the predominant skin NKT cells were CXCR4+ and CD69+. Skin-resident NKT cells uniquely expressed CXCR4, unlike NKT cells in the liver, spleen, and lymph nodes. Skin fibroblasts were the main source of CXCL12. CXCR4+ NKT cells preferentially trafficked to CXCL12-rich areas, forming an enriched CXCR4+ tissue-resident NKT cells/CXCL12+ cell cluster that developed in acute and chronic allergic inflammation in our models of mice with AD. CONCLUSIONS: CXCR4+ tissue-resident NKT cells may form a niche that contributes to AD, in which CXCL12 is highly expressed.
Subject(s)
Chemokine CXCL12/immunology , Dermatitis, Atopic/immunology , Natural Killer T-Cells/immunology , Receptors, CXCR4/immunology , Skin/immunology , Animals , Chemokine CXCL12/genetics , Dermatitis, Atopic/genetics , Female , Gene Expression Profiling , Humans , Mice , Proteomics , Receptors, CXCR4/geneticsABSTRACT
Recent studies have demonstrated that the skin of a normal adult human contains 10-20 billion resident memory T cells, including various helper, cytotoxic, and regulatory T cell subsets, that are poised to respond to environmental antigens. Using only autologous human tissues, we report that both in vitro and in vivo, resting epidermal Langerhan cells (LCs) selectively and specifically induced the activation and proliferation of skin resident regulatory T (Treg) cells, a minor subset of skin resident memory T cells. In the presence of foreign pathogen, however, the same LCs activated and induced proliferation of effector memory T (Tem) cells and limited Treg cells' activation. These underappreciated properties of LCs, namely maintenance of tolerance in normal skin, and activation of protective skin resident memory T cells upon infectious challenge, help clarify the role of LCs in skin.
Subject(s)
Epidermis/immunology , Langerhans Cells/immunology , Skin/immunology , T-Lymphocytes, Regulatory/immunology , Antigens/immunology , Cell Growth Processes/immunology , Homeostasis/immunology , Humans , Immunologic Memory/immunology , Lymphocyte Activation/immunology , Skin/cytologyABSTRACT
BACKGROUND: Candida albicans is a dimorphic fungus to which human subjects are exposed early in life, and by adulthood, it is part of the mycobiome of skin and other tissues. Neonatal skin lacks resident memory T (TRM) cells, but in adults the C albicans skin test is a surrogate for immunocompetence. Young adult mice raised under specific pathogen-free conditions are naive to C albicans and have been shown recently to have an immune system resembling that of neonatal human subjects. OBJECTIVE: We studied the evolution of the adaptive cutaneous immune response to Candida species. METHODS: We examined both human skin T cells and the de novo and memory immune responses in a mouse model of C albicans skin infection. RESULTS: In mice the initial IL-17-producing cells after C albicans infection were dermal γδ T cells, but by day 7, αß TH17 effector T cells were predominant. By day 30, the majority of C albicans-reactive IL-17-producing T cells were CD4 TRM cells. Intravital microscopy showed that CD4 effector T cells were recruited to the site of primary infection and were highly motile 10 days after infection. Between 30 and 90 days after infection, these CD4 T cells became increasingly sessile, acquired expression of CD69 and CD103, and localized to the papillary dermis. These established TRM cells produced IL-17 on challenge, whereas motile migratory memory T cells did not. TRM cells rapidly clear an infectious challenge with C albicans more effectively than recirculating T cells, although both populations participate. We found that in normal human skin IL-17-producing CD4+ TRM cells that responded to C albicans in an MHC class II-restricted fashion could be identified readily. CONCLUSIONS: These studies demonstrate that C albicans infection of skin preferentially generates CD4+ IL-17-producing TRM cells, which mediate durable protective immunity.
Subject(s)
Candida albicans/physiology , Candidiasis/immunology , Skin/immunology , T-Lymphocyte Subsets/physiology , Th17 Cells/physiology , Adaptive Immunity , Adult , Animals , Cell Differentiation , Cell Movement , Cells, Cultured , Disease Models, Animal , Humans , Immunocompetence , Immunologic Memory , Infant, Newborn , Interleukin-17/metabolism , Mice , Mice, Inbred C57BL , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Skin/microbiologyABSTRACT
Protective T-cell memory has long been thought to reside in blood and lymph nodes, but recently the concept of immune memory in peripheral tissues mediated by resident memory T (T(RM)) cells has been proposed. Here we show in mice that localized vaccinia virus (VACV) skin infection generates long-lived non-recirculating CD8(+) skin T(RM) cells that reside within the entire skin. These skin T(RM) cells are potent effector cells, and are superior to circulating central memory T (T(CM)) cells at providing rapid long-term protection against cutaneous re-infection. We find that CD8(+) T cells are rapidly recruited to skin after acute VACV infection. CD8(+) T-cell recruitment to skin is independent of CD4(+) T cells and interferon-γ, but requires the expression of E- and P-selectin ligands by CD8(+) T cells. Using parabiotic mice, we further show that circulating CD8(+) T(CM) and CD8(+) skin T(RM) cells are both generated after skin infection; however, CD8(+) T(CM) cells recirculate between blood and lymph nodes whereas T(RM) cells remain in the skin. Cutaneous CD8(+) T(RM) cells produce effector cytokines and persist for at least 6 months after infection. Mice with CD8(+) skin T(RM) cells rapidly cleared a subsequent re-infection with VACV whereas mice with circulating T(CM) but no skin T(RM) cells showed greatly impaired viral clearance, indicating that T(RM) cells provide superior protection. Finally, we show that T(RM) cells generated as a result of localized VACV skin infection reside not only in the site of infection, but also populate the entire skin surface and remain present for many months. Repeated re-infections lead to progressive accumulation of highly protective T(RM) cells in non-involved skin. These findings have important implications for our understanding of protective immune memory at epithelial interfaces with the environment, and suggest novel strategies for vaccines that protect against tissue tropic organisms.
Subject(s)
CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Immunologic Memory/immunology , Skin/immunology , Skin/virology , Animals , CD4-Positive T-Lymphocytes , Cell Movement , E-Selectin/metabolism , Female , Interferon-gamma , Mice , Mice, Inbred C57BL , Models, Immunological , P-Selectin/metabolism , Skin/metabolism , Vaccinia/immunology , Vaccinia/virology , Vaccinia virus/immunology , Vaccinia virus/physiologyABSTRACT
Interleukin 4 (IL-4) can suppress delayed-type hypersensitivity reactions (DTHRs), including organ-specific autoimmune diseases in mice and humans. Despite the broadly documented antiinflammatory effect of IL-4, the underlying mode of action remains incompletely understood, as IL-4 also promotes IL-12 production by dendritic cells (DCs) and IFN-γ-producing T(H)1 cells in vivo. Studying the impact of IL-4 on the polarization of human and mouse DCs, we found that IL-4 exerts opposing effects on the production of either IL-12 or IL-23. While promoting IL-12-producing capacity of DCs, IL-4 completely abrogates IL-23. Bone marrow chimeras proved that IL-4-mediated suppression of DTHRs relies on the signal transducer and activator of transcription 6 (STAT6)-dependent abrogation of IL-23 in antigen-presenting cells. Moreover, IL-4 therapy attenuated DTHRs by STAT6- and activating transcription factor 3 (ATF3)-dependent suppression of the IL-23/T(H)17 responses despite simultaneous enhancement of IL-12/TH1 responses. As IL-4 therapy also improves psoriasis in humans and suppresses IL-23/T(H)17 responses without blocking IL-12/T(H)1, selective IL-4-mediated IL-23/T(H)17 silencing is promising as treatment against harmful inflammation, while sparing the IL-12-dependent T(H)1 responses.
Subject(s)
Antigen-Presenting Cells/immunology , Gene Silencing , Inflammation/physiopathology , Interleukin-23/genetics , Interleukin-4/physiology , Th17 Cells/immunology , HumansABSTRACT
Cutaneous T-cell lymphoma (CTCL) is an aggressive neoplasm with limited treatments for patients with advanced disease. The mucin 1 C-terminal subunit (MUC1-C) oncoprotein plays a critical role in regulating cell proliferation, apoptosis, and protection from cytotoxic injury mediated by reactive oxygen species (ROS). Although CTCL cells exhibit resistance to ROS-induced apoptosis, the expression and functional significance of MUC1 in CTCL have not been previously investigated. Present studies demonstrate that MUC1-C is overexpressed in CTCL cell lines and primary CTCL cells but is absent in resting T cells from healthy donors and B-cell lymphoma cells. We have developed a cell-penetrating peptide that disrupts homodimerization of the MUC1-C subunit necessary for its nuclear translocation and downstream signaling. We show that treatment of CTCL cells with the MUC1-C inhibitor is associated with downregulation of the p53-inducible regulator of glycolysis and apoptosis and decreases in reduced NAD phosphate and glutathione levels. In concert with these results, targeting MUC1-C in CTCL cells increased ROS and, in turn, induced ROS-mediated late apoptosis/necrosis. Targeting MUC1-C in CTCL tumor xenograft models demonstrated significant decreases in disease burden. These findings indicate that MUC1-C maintains redox balance in CTCL cells and is thereby a novel target for the treatment of patients with CTCL.
Subject(s)
Apoptosis/drug effects , Cell Proliferation/drug effects , Lymphoma, T-Cell, Cutaneous/metabolism , Mucin-1/metabolism , Peptides/pharmacology , Skin Neoplasms/metabolism , Animals , Apoptosis Regulatory Proteins , Blotting, Western , Case-Control Studies , Female , Flow Cytometry , Glutathione/metabolism , Humans , Immunoenzyme Techniques , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Lymphoma, T-Cell, Cutaneous/drug therapy , Lymphoma, T-Cell, Cutaneous/pathology , Mice , Mice, Inbred NOD , Mice, SCID , Mucin-1/chemistry , Mucin-1/genetics , NADP/metabolism , Necrosis , Oxidative Stress , Phosphoric Monoester Hydrolases , RNA, Messenger/genetics , Reactive Oxygen Species/metabolism , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Early-stage cutaneous T-cell lymphoma (CTCL) is a skin-limited lymphoma with no cure aside from stem cell transplantation. Twelve patients with stage IA-IIA CTCL were treated in a phase 1 trial of 0.03% and 0.06% topical resiquimod gel, a Toll-like receptor 7/8 agonist. Treated lesions significantly improved in 75% of patients and 30% had clearing of all treated lesions. Resiquimod also induced regression of untreated lesions. Ninety-two percent of patients had more than a 50% improvement in body surface area involvement by the modified Severity-Weighted Assessment Tool analysis and 2 patients experienced complete clearing of disease. Four of 5 patients with folliculotropic disease also improved significantly. Adverse effects were minor and largely skin limited. T-cell receptor sequencing and flow cytometry studies of T cells from treated lesions demonstrated decreased clonal malignant T cells in 90% of patients and complete eradication of malignant T cells in 30%. High responses were associated with recruitment and expansion of benign T-cell clones in treated skin, increased skin T-cell effector functions, and a trend toward increased natural killer cell functions. In patients with complete or near eradication of malignant T cells, residual clinical inflammation was associated with cytokine production by benign T cells. Fifty percent of patients had increased activation of circulating dendritic cells, consistent with a systemic response to therapy. In summary, topical resiquimod is safe and effective in early-stage CTCL and the first topical therapy to our knowledge that can induce clearance of untreated lesions and complete remissions in some patients. This trial was registered at www.clinicaltrials.gov as #NCT813320.
Subject(s)
Antineoplastic Agents/therapeutic use , Imidazoles/therapeutic use , Lymphoma, T-Cell, Cutaneous/drug therapy , Skin Neoplasms/drug therapy , Skin/drug effects , T-Lymphocytes/drug effects , Administration, Topical , Adult , Aged , Antineoplastic Agents/administration & dosage , Female , Humans , Imidazoles/administration & dosage , Lymphoma, T-Cell, Cutaneous/immunology , Lymphoma, T-Cell, Cutaneous/pathology , Male , Middle Aged , Skin/immunology , Skin/pathology , Skin Neoplasms/immunology , Skin Neoplasms/pathology , T-Lymphocytes/immunology , T-Lymphocytes/pathologyABSTRACT
INTRODUCTION: Infiltration of cancers by T cells is associated with improved patient survival and response to immune therapies; however, optimal approaches to induce T cell infiltration of tumors are not known. This study was designed to assess whether topical treatment of melanoma metastases with the TLR7 agonist imiquimod plus administration of a multipeptide cancer vaccine will improve immune cell infiltration of melanoma metastases. PATIENTS AND METHODS: Eligible patients were immunized with a vaccine comprised of 12 melanoma peptides and a tetanus toxoid-derived helper peptide, and imiquimod was applied topically to metastatic tumors daily. Adverse events were recorded, and effects on the tumor microenvironment were evaluated from sequential tumor biopsies. T cell responses were assessed by IFNγ ELIspot assay and T cell tetramer staining. Patient tumors were evaluated for immune cell infiltration, cytokine and chemokine production, and gene expression. RESULTS AND CONCLUSIONS: Four eligible patients were enrolled, and administration of imiquimod and vaccination were well tolerated. Circulating T cell responses to the vaccine was detected by ex vivo ELIspot assay in 3 of 4 patients. Treatment of metastases with imiquimod induced immune cell infiltration and favorable gene signatures in the patients with circulating T cell responses. This study supports further study of topical imiquimod combined with vaccines or other immune therapies for the treatment of melanoma.
Subject(s)
Aminoquinolines/therapeutic use , Antigens, Neoplasm/immunology , Antineoplastic Agents/therapeutic use , Cancer Vaccines/immunology , Melanoma/therapy , Peptide Fragments/immunology , Skin Neoplasms/therapy , T-Lymphocytes/drug effects , Administration, Topical , Aged , Cell Movement/drug effects , Cells, Cultured , Combined Modality Therapy , Cytokines/genetics , Cytokines/metabolism , Enzyme-Linked Immunospot Assay , Female , Humans , Imiquimod , Lymphocytes, Tumor-Infiltrating/pathology , Male , Melanoma/secondary , Middle Aged , Neoplasm Staging , Skin Neoplasms/secondary , T-Lymphocytes/immunology , Toll-Like Receptor 7/agonists , Transcriptome/immunology , Vaccines, Subunit/immunologyABSTRACT
BACKGROUND: Alemtuzumab is a humanized monoclonal antibody directed against CD52, a cell surface antigen on B and T lymphocytes, and used to treat B-cell chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Skin rash is a common adverse reaction following treatment with alemtuzumab. However, the clinicopathologic features and immunologic basis for the reaction have not been previously reported. METHODS: Our hospital's electronic pathology database was searched for cases with documentation of 'alemtuzumab' or 'anti-CD52' in the clinical history provided by either the ordering physician or the pathologist. Clinical and histopathologic review of the cases was performed. RESULTS: Five patients with cutaneous T-cell lymphoma (CTCL) or chronic lymphocytic leukemia (CLL) were treated with alemtuzumab, and developed pruritic, erythematous papules and plaques. Histopathology of the skin lesions revealed subacute spongiotic dermatitis with multifocal parakeratosis, endothelial activation and perivascular lymphocytic infiltrate. Eosinophils were not a prominent feature. CONCLUSIONS: We describe the clinicopathologic features of a novel hypersensitivity reaction to alemtuzumb, and hypothesize it may be due to an immunologic response precipitated by the persistence of resident memory T-cells (TRM ) in the skin. Our findings raise awareness for a novel reaction pattern and guide the histopathologic interpretation of lesions which may clinically mimic residual or recurrent cutaneous lymphoproliferative disorders.
Subject(s)
Antibodies, Monoclonal, Humanized/immunology , Dermatitis/etiology , Drug Hypersensitivity/pathology , Aged , Aged, 80 and over , Alemtuzumab , Antibodies, Monoclonal, Humanized/administration & dosage , Dermatitis/pathology , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Lymphoma, T-Cell, Cutaneous/drug therapy , MaleABSTRACT
Tumor-derived galectin-1 (Gal-1), a ß-galactoside-binding S-type lectin, has been shown to encourage T-cell death and promote T cell-mediated tumor immune escape. In this report, we show that patients with leukemic cutaneous T-cell lymphomas, known to have limited complexity of their T-cell repertoires, have a predominant T helper type-2 (Th2) cytokine profile and significantly elevated plasma levels of Gal-1 compared with healthy controls. Circulating clonal malignant T cells were a major source of Gal-1. The conditioned supernatant of cultured malignant T cells induced a ß-galactoside-dependent inhibition of normal T-cell proliferation and a Th2 skewing of cytokine production. These data implicate Gal-1 in development of the Th2 phenotype in patients with advanced-stage cutaneous T-cell lymphoma and highlight the Gal-1-Gal-1 ligand axis as a potential therapeutic target for enhancing antitumor immune responses.
Subject(s)
Cell Proliferation , Galectin 1/physiology , Leukemia, T-Cell/immunology , Lymphoma, T-Cell, Cutaneous/immunology , Skin Neoplasms/immunology , T-Lymphocytes/physiology , Th1 Cells/physiology , Cell Survival/immunology , Cells, Cultured , Female , Flow Cytometry , Galectin 1/metabolism , Gene Expression Regulation, Leukemic , Humans , Leukemia, T-Cell/metabolism , Leukemia, T-Cell/pathology , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/pathology , Leukocytes, Mononuclear/physiology , Lymphoma, T-Cell, Cutaneous/metabolism , Lymphoma, T-Cell, Cutaneous/pathology , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , T-Lymphocytes/metabolism , Th1 Cells/metabolism , Th1 Cells/pathologyABSTRACT
Type 2-polarized memory B cells sustain food allergy and allergic rhinitis by rapidly differentiating into pathogenic IgE-producing plasma cells.
Subject(s)
Immunoglobulin E , Rhinitis, Allergic , Humans , B-Lymphocytes , Plasma Cells , Memory B CellsABSTRACT
Virus and T cell inflammation persist in the tissues of patients with Long Covid.
Subject(s)
COVID-19 , Inflammation , SARS-CoV-2 , T-Lymphocytes , COVID-19/immunology , Humans , SARS-CoV-2/immunology , Inflammation/immunology , T-Lymphocytes/immunologyABSTRACT
Human Langerhans cells highly express CD1a antigen-presenting molecules. To understand the functions of CD1a in human skin, we used CD1a tetramers to capture T cells and determine their effector functions and TCR patterns. Skin T cells from all donors showed CD1a tetramer staining, which in three cases exceeded 10% of skin T cells. CD1a tetramer-positive T cells produced diverse cytokines, including IL-2, IL-4, IL-5, IL-9, IL-17, IL-22, and IFN-γ. Conserved TCRs often recognize nonpolymorphic antigen-presenting molecules, but no TCR motifs are known for CD1a. We detected highly conserved TCRs that used TRAV34 and TRBV28 variable genes, which is a known motif for recognition of staphylococcal enterotoxin B, a superantigen associated with atopic dermatitis. We found that these conserved TCRs did not respond to superantigen presented by CD1a, but instead showed a cross-reactive response with two targets: CD1a and staphylococcal enterotoxin B presented by classical major histocompatibility complex II. These studies identify a conserved human TCR motif for CD1a-reactive T cells. Furthermore, the demonstrated cross-reaction of T cells with two common skin-specific stimuli suggests a candidate mechanism by which CD1a and skin flora could synergize during natural immune response and in Staphylococcus-associated skin diseases.