ABSTRACT
Renal clear cell carcinoma (RCC) is a type of malignant tumor, which, in addition to surgical resection, radiotherapy, and chemotherapy, has been widely treated through immunotherapy recently. However, the influence of the tumor microenvironment and the infiltrating immune cells within it on immunotherapy remains unclear. It is imperative to study the interactions between various immune cells of RCC. The scRNA-seq dataset from GEO's database was used to analyze the immune cells present in tumor tissue and peripheral blood samples. Through quality control, clustering, and identification, the types and proportions of infiltrating immune cells were determined. The cellular differences were determined, and gene expression levels of the differentially present cells were investigated. A protein-protein interaction network analysis was performed using string. KEGG and GO analyses were performed to investigate abnormal activities. The microglia marker CD68 and CD1C+ B dendritic cells marker CD11C were detected using multiplex immunofluorescence staining. Many depleted CD8+ T cells (exhausted CD8+ T cells) appeared in tumor tissues as well as microglia. CD1C+ B dendritic cells did not infiltrate tumor tissues. HSPA1A was correlated with DNAJB1 in microglia. Compared with Paracancer tissues, microglia increased while CD1C+ B dendritic cells decreased in pathological stages I and I-II in cancerous tissues. An altered tumor microenvironment caused by increases in microglia in RCC in the early stage resulted in an inability of CD1C+ B dendritic cells to infiltrate, resulting in CD8+ T cells being unable to receive the antigens presented by them, and in turn being depleted in large quantities.
Subject(s)
Antigens, CD1 , CD8-Positive T-Lymphocytes , Carcinoma, Renal Cell , Dendritic Cells , Kidney Neoplasms , Microglia , Tumor Microenvironment , Humans , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/immunology , Kidney Neoplasms/pathology , Dendritic Cells/immunology , Dendritic Cells/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Tumor Microenvironment/immunology , Microglia/immunology , Microglia/metabolism , Antigens, CD1/metabolism , Male , Neoplasm Staging , Female , GlycoproteinsABSTRACT
Addressing the mononuclear phagocyte system (MPS) and macrophage M1/M2 activation is important in diagnosing hematological disorders and inflammatory pathologies and designing therapeutic tools. CSF1R is a reliable marker to identify all circulating MPS cells and tissue macrophages in humans using a single surface protein. CSF1R permits the quantification and isolation of monocyte and dendritic cell (DC) subsets in conjunction with CD14, CD16, and CD1c and is stable across the lifespan and sexes in the absence of overt pathology. Beyond cell detection, measuring M1/M2 activation in humans poses challenges due to response heterogeneity, transient signaling, and multiple regulation steps for transcripts and proteins. MPS cells respond in a conserved manner to M1/M2 pathways such as interleukin-4 (IL-4), steroids, interferon-γ (IFNγ), and lipopolysaccharide (LPS), for which we propose an ad hoc modular gene expression tool. Signature analysis highlights macrophage activation mosaicism in experimental samples, an emerging concept that points to mixed macrophage activation states in pathology.
Subject(s)
Macrophage Activation , Macrophages , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor , Humans , Macrophage Activation/genetics , Macrophages/metabolism , Macrophages/immunology , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Interferon-gamma/metabolism , Lipopolysaccharides/pharmacology , Female , Mosaicism , Male , Monocytes/metabolism , Lipopolysaccharide Receptors/metabolism , Interleukin-4/metabolism , Dendritic Cells/metabolism , Dendritic Cells/immunology , Receptors, IgG/metabolism , Receptors, IgG/genetics , Antigens, CD1/metabolism , Antigens, CD1/genetics , Mononuclear Phagocyte System/metabolism , Glycoproteins , Receptor, Macrophage Colony-Stimulating FactorABSTRACT
CD1 molecules are well known for their role in binding and presenting lipid antigens to mediate the activation of CD1-restricted T cells. However, much less appreciated is the fact that CD1 molecules can have additional "unconventional" roles which impact the activation and functions of CD1-expressing cells, ultimately controlling tissue homeostasis as well as the progression of inflammatory and infectious diseases. Some of these roles are mediated by so-called reverse signalling, by which crosslinking of CD1 molecules at the cell surface initiates intracellular signalling. On the other hand, CD1 molecules can also control metabolic and inflammatory pathways in CD1-expressing cells through cell-intrinsic mechanisms independent of CD1 ligation. Here, we review the evidence for "unconventional" functions of CD1 molecules and the outcomes of such roles for health and disease.
Subject(s)
Antigen Presentation , Antigens, CD1 , Animals , Humans , Antigens, CD1/metabolism , Inflammation/immunology , Lymphocyte Activation , Signal Transduction , T-Lymphocytes/immunologyABSTRACT
Langerhans cell histiocytosis (LCH) is characterized by an expansion and accumulation of pathological histiocytes expressing langerin (CD207) and CD1a in different organs under an inflammatory milieu. The origin of pathognomonic precursors of LCH is widely debated, but monocytes and pre-dendritic cells (pre-DC) play a significant role. Remarkably, we found an expansion of AXLhigh cells in the CD11c+ subset of patients with active LCH, which also express the pathognomonic CD207 and CD1a. Moreover, we obtained a monocyte-derived LC-like (mo-LC-like) expressing high levels of AXL when treated with inflammatory cytokine, or plasma of patients with active disease. Intriguingly, inhibiting the mTOR pathway at the initial stages of monocyte differentiation to LC-like fosters the pathognomonic LCH program, highly increasing CD207 levels, together with NOTCH1 induction. We define here that AXLhigh could also be taken as a strong pathognomonic marker for LCH, and the release of Langerin and NOTCH1 expression depends on the inhibition of the mTOR pathway.
Subject(s)
Antigens, CD , Axl Receptor Tyrosine Kinase , Histiocytosis, Langerhans-Cell , Lectins, C-Type , Mannose-Binding Lectins , Proto-Oncogene Proteins , Receptor Protein-Tyrosine Kinases , TOR Serine-Threonine Kinases , Humans , Histiocytosis, Langerhans-Cell/metabolism , TOR Serine-Threonine Kinases/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Antigens, CD/metabolism , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins/genetics , Mannose-Binding Lectins/metabolism , Lectins, C-Type/metabolism , Male , Myeloid Cells/metabolism , Biomarkers , Female , Adolescent , Receptor, Notch1/metabolism , Antigens, CD1/metabolism , Child , Monocytes/metabolism , Monocytes/immunology , Adult , Child, Preschool , Signal Transduction , Cell DifferentiationABSTRACT
The CD1 and MR1 protein families present lipid antigens and small molecules to T cells, complementing well-studied major histocompatibility complex-peptide mechanisms. The CD1a subtype is highly and continuously expressed within the skin, most notably on Langerhans cells, and has been demonstrated to present self and foreign lipids to T cells, highlighting its cutaneous sentinel role. Alteration of CD1a-dependent T-cell responses has recently been discovered to contribute to the pathogenesis of several inflammatory skin diseases. In this review, we overview the structure and role of CD1a and outline the current evidence implicating CD1a in the development of psoriasis, atopic dermatitis and allergic contact dermatitis.
Subject(s)
Antigens, CD1 , Skin Diseases , T-Lymphocytes , Humans , Antigens, CD1/metabolism , Antigens, CD1/immunology , Dermatitis, Allergic Contact/immunology , Dermatitis, Atopic/immunology , Langerhans Cells/immunology , Psoriasis/immunology , Skin/immunology , Skin/pathology , T-Lymphocytes/immunology , Skin Diseases/drug therapy , Skin Diseases/metabolism , Skin Diseases/pathologyABSTRACT
Invariant natural killer T (NKT) cell subsets are defined based on their cytokine-production profiles and transcription factors. Their distribution is different in C57BL/6 (B6) and BALB/c mice, with a bias for NKT1 and NKT2/NKT17 subsets, respectively. Here, we show that the non-classical class I-like major histocompatibility complex CD1 molecules CD1d2, expressed in BALB/c and not in B6 mice, could not account for this difference. We find however that NKT cell subset distribution is intrinsic to bone marrow derived NKT cells, regardless of syngeneic CD1d-ligand recognition, and that multiple intrinsic factors are likely involved. Finally, we find that CD1d expression levels in combination with T cell antigen receptor signal strength could also influence NKT cell distribution and function. Overall, this study indicates that CD1d-mediated TCR signals and other intrinsic signals integrate to influence strain-specific NKT cell differentiation programs and subset distributions.
Subject(s)
Natural Killer T-Cells , Animals , Mice , Antigens, CD1/metabolism , Antigens, CD1d/metabolism , Cell Differentiation , Killer Cells, Natural , Mice, Inbred C57BL , Receptors, Antigen, T-Cell/metabolism , T-Lymphocyte SubsetsABSTRACT
Humans express four different lipid antigen-presenting molecules, CD1a, CD1b, CD1c, and CD1d, that are differentially expressed on antigen-presenting cells and which recycle through different endosomal compartments. Huang et al. now answer the question on whether the four CD1 isoforms selectively bind certain lipids.
Subject(s)
Antigens, CD1 , Lipids , Humans , Antigen Presentation , Antigens, CD1/metabolism , Protein Isoforms/metabolism , Antigens, CD1d/metabolismABSTRACT
The CD1 system binds lipid antigens for display to T cells. Here, we solved lipidomes for the four human CD1 antigen-presenting molecules, providing a map of self-lipid display. Answering a basic question, the detection of >2,000 CD1-lipid complexes demonstrates broad presentation of self-sphingolipids and phospholipids. Whereas peptide antigens are chemically processed, many lipids are presented in an unaltered form. However, each type of CD1 protein differentially edits the self-lipidome to show distinct capture motifs based on lipid length and chemical composition, suggesting general antigen display mechanisms. For CD1a and CD1d, lipid size matches the CD1 cleft volume. CD1c cleft size is more variable, and CD1b is the outlier, where ligands and clefts show an extreme size mismatch that is explained by uniformly seating two small lipids in one cleft. Furthermore, the list of compounds that comprise the integrated CD1 lipidome supports the ongoing discovery of lipid blockers and antigens for T cells.
Subject(s)
Antigens, CD1 , Lipids , Humans , Antigen Presentation , Antigens, CD1/chemistry , Antigens, CD1/metabolism , Lipidomics , Lipids/chemistry , T-Lymphocytes , Amino Acid MotifsABSTRACT
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
After two decades of the study of lipid antigens that activate CD1-restricted T cells, new studies show how autoreactive αß T-cell receptors (TCRs) can directly recognize the outer surface of CD1 proteins in ways that are lipid-agnostic. Most recently, this lipid agnosticism has turned to negativity, with the discovery of natural CD1 ligands that dominantly negatively block autoreactive αß TCR binding to CD1a and CD1d. This review highlights the basic differences between positive and negative regulation of cellular systems. We outline strategies to discover lipid inhibitors of CD1-reactive T cells, whose roles in vivo are becoming clear, especially in CD1-mediated skin disease.
Subject(s)
Antigen Presentation , T-Lymphocytes , Humans , Receptors, Antigen, T-Cell/metabolism , Antigens , Lipids , Antigens, CD1/metabolismABSTRACT
CD1 glycoproteins present lipid-based antigens to T-cell receptors (TCRs). A role for CD1b in T-cell-mediated autoreactivity was proposed when it was established that CD1b can present self-phospholipids with short alkyl chains (â¼C34) to T cells; however, the structural characteristics of this presentation and recognition are unclear. Here, we report the 1.9 Å resolution binary crystal structure of CD1b presenting a self-phosphatidylinositol-C34:1 and an endogenous scaffold lipid. Moreover, we also determined the 2.4 Å structure of CD1b-phosphatidylinositol complexed to an autoreactive αß TCR, BC8B. We show that the TCR docks above CD1b and directly contacts the presented antigen, selecting for both the phosphoinositol headgroup and glycerol neck region via antigen remodeling within CD1b and allowing lateral escape of the inositol moiety through a channel formed by the TCR α-chain. Furthermore, through alanine scanning mutagenesis and surface plasmon resonance, we identified key CD1b residues mediating this interaction, with Glu-80 abolishing TCR binding. We in addition define a role for both CD1b α1 and CD1b α2 molecular domains in modulating this interaction. These findings suggest that the BC8B TCR contacts both the presented phospholipid and the endogenous scaffold lipid via a dual mechanism of corecognition. Taken together, these data expand our understanding into the molecular mechanisms of CD1b-mediated T-cell autoreactivity.
Subject(s)
Antigen Presentation , Antigens, CD1 , Phosphatidylinositols , Receptors, Antigen, T-Cell , T-Lymphocytes , Antigens, CD1/metabolism , Phospholipids/metabolism , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes/metabolismABSTRACT
CD1 molecules and the MHC-related protein 1 (MR1) present lipid and small molecule antigens, respectively, for T cell surveillance. The biology of these molecules, the antigens they present, and the T cells that respond to them were recently discussed during the 12th International CD1-MR1 Meeting held in Gothenburg, Sweden.
Subject(s)
Antigens, CD1 , Histocompatibility Antigens Class I , Minor Histocompatibility Antigens , Antigens, CD1/metabolism , T-Lymphocytes , Antigens , Antigen PresentationABSTRACT
The individual contribution of specific myeloid subsets such as CD1c+ conventional DC (cDC) to perpetuation of rheumatoid arthritis (RA) pathology remains unclear. In addition, the specific innate sensors driving pathogenic activation of CD1c+ cDC in patients with RA and their functional implications have not been characterized. Here, we assessed phenotypical, transcriptional, and functional characteristics of CD1c+ and CD141+ cDC and monocytes from the blood and synovial fluid of patients with RA. Increased levels of CCR2 and the IgG receptor CD64 on circulating CD1c+ cDC was associated with the presence of this DC subset in the synovial membrane in patients with RA. Moreover, synovial CD1c+ cDC are characterized by increased expression of proinflammatory cytokines and high abilities to induce pathogenic IFN-γ+IL-17+CD4+ T cells in vitro. Finally, we identified the crosstalk between Fcγ receptors and NLRC4 as a potential molecular mechanism mediating pathogenic activation, CD64 upregulation, and functional specialization of CD1c+ cDC in response to dsDNA-IgG in patients with RA.
Subject(s)
Arthritis, Rheumatoid , Dendritic Cells , Humans , Dendritic Cells/metabolism , Arthritis, Rheumatoid/metabolism , Synovial Membrane/pathology , Synovial Fluid , Cytokines/metabolism , Calcium-Binding Proteins/metabolism , CARD Signaling Adaptor Proteins , Glycoproteins/metabolism , Antigens, CD1/metabolismABSTRACT
Langerhans cell histiocytosis (LCH) is a disorder characterized by an abnormal accumulation of CD207+ and CD1a+ cells in almost any tissue. Currently, there is a lack of prognostic markers to follow up patients and track disease reactivation or treatment response. Putative myeloid precursors CD207+ and CD1a+ cells were previously identified circulating in the blood. Therefore, we aim to develop a sensitive tracing method to monitor circulating CD207+ and CD1a+ cells in a drop of blood sample of patients with LCH. A total of 202 blood samples from patients with LCH and 23 controls were tested using flow cytometry. A standardized cellular score was defined by quantifying CD207+ and CD1a+ expression in monocytes and dendritic cells, based on CD11b, CD14, CD11c, and CD1c subpopulations, resulting in a unique value for each sample. The scoring system was validated by a receiver operating characteristic curve showing a reliable discriminatory capacity (area under the curve of 0.849) with a threshold value of 14, defining the presence of circulating CD207+ and CD1a+ cells. Interestingly, a fraction of patients with no evident clinical manifestation at the time of sampling also showed presence of these cells (29.6%). We also found a differential expression of CD207 and CD1a depending on the organ involvement, and a positive correlation between the cellular score and plasma inflammatory markers such as soluble CD40L, soluble IL-2Ra, and CXCL12. In conclusion, the analysis of circulating CD207 and CD1a cells in a small blood sample will allow setting a cellular score with minimal invasiveness, helping with prognostic accuracy, detecting early reactivation, and follow-up.
Subject(s)
Histiocytosis, Langerhans-Cell , Mannose-Binding Lectins , Antigens, CD/metabolism , Antigens, CD1/metabolism , Histiocytosis, Langerhans-Cell/diagnosis , Histiocytosis, Langerhans-Cell/metabolism , Humans , Langerhans Cells , Lectins, C-Type/metabolism , Mannose-Binding Lectins/metabolismABSTRACT
Inhibition of sodium-glucose cotransporter-2 (SGLT2) has been shown to be a safe and efficacious approach to support managing Type 2 diabetes. In the 2-year carcinogenicity study with the SGLT2 inhibitor empagliflozin in CD-1 mice, an increased incidence of renal tubular adenomas and carcinomas was identified in the male high-dose group but was not observed in female mice. An integrated review of available nonclinical data was conducted to establish a mode-of-action hypothesis for male mouse-specific tumorigenesis. Five key events were identified through systematic analysis to form the proposed mode-of-action: (1) Background kidney pathology in CD-1 mice sensitizes the strain to (2) pharmacology-related diuretic effects associated with SGLT2 inhib ition. (3) In male mice, metabolic demand increases with the formation of a sex- and species-specific empagliflozin metabolite. These features converge to (4) deplete oxidative stress handling reserve, driving (5) constitutive cellular proliferation in male CD-1 mice. The proposed mode of action requires all five key events for empagliflozin to present a carcinogenicity risk in the CD-1 mouse. Considering that empagliflozin is not genotoxic in the standard battery of genotoxicity tests, and not all five key events are present in the context of female mice, rats, or humans, nor for other osmotic diuretics or other SGLT2 inhibitors, the observed male mouse renal tumors are not considered relevant to humans.
Subject(s)
Carcinoma, Renal Cell , Diabetes Mellitus, Type 2 , Kidney Neoplasms , Sodium-Glucose Transporter 2 Inhibitors , Animals , Antigens, CD1/metabolism , Benzhydryl Compounds/toxicity , Carcinoma, Renal Cell/complications , Carcinoma, Renal Cell/pathology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/pathology , Female , Glucosides , Humans , Hypoglycemic Agents/toxicity , Kidney , Kidney Neoplasms/chemically induced , Kidney Neoplasms/complications , Kidney Neoplasms/drug therapy , Male , Mice , Rats , Sodium-Glucose Transporter 2/metabolism , Sodium-Glucose Transporter 2/pharmacology , Sodium-Glucose Transporter 2 Inhibitors/toxicityABSTRACT
T-VEC, a HSV-1 derived oncolytic virus, is approved for the treatment of advanced melanoma. The mechanisms that underly the systemic anti-tumor effect that is seen following intratumoral injection have not yet been studied but are likely to be mediated by myeloid dendritic cells (myDC) that initiate an adaptive immune response. In this study we could demonstrate that T-VEC is non-toxic for human myDC. T-VEC and a T-VEC oncolysate of melanoma cell lines were able to mature human myDC. myDC were able to take up lysed melanoma cells and cross-present melanoma-derived tumor antigens to antigen-specific T cells. Our results support the possible role of myDC as mediators of an adaptive anti-tumor effect and intratumoral co-administration of T-VEC plus autologous myDC could be a complementary treatment option. A clinical trial that investigates this hypothesis is currently ongoing.
Subject(s)
Antineoplastic Agents, Immunological/pharmacology , Biological Products/pharmacology , Dendritic Cells/immunology , Immunotherapy/methods , Melanoma/therapy , Myeloid Cells/immunology , T-Lymphocytes/immunology , Adaptive Immunity , Antigens, CD1/metabolism , Antigens, Neoplasm/immunology , Cross-Priming , Glycoproteins/metabolism , Herpesvirus 1, Human , Humans , Lymphocyte Activation , Melanoma/immunology , Oncolytic Virotherapy , Phagocytosis , T-Lymphocytes/drug effectsABSTRACT
Cellular senescence is more than a proliferative arrest in response to various stimuli. Senescent cells (SC) participate in several physiological processes, and their adequate removal is essential to maintain tissue and organism homeostasis. However, SC accumulation in aging and age-related diseases alters the tissue microenvironment leading to deterioration. The immune system clears the SC, but the specific scenarios and mechanisms related to recognizing and eliminating them are unknown. Hence, we aimed to evaluate the existence of three regulatory signals of phagocytic function, CD47, major histocompatibility complex class I (MHC-I), and calreticulin, present in the membrane of SC. Therefore, primary fibroblasts were isolated from CD1 female mice lungs, and stress-induced premature senescence (SIPS) was induced with hydrogen peroxide. Replicative senescence (RS) was used as a second senescent model. Our results revealed a considerable increment of CD47 and MHC-I in RS and SIPS fibroblasts. At the same time, no significant changes were found in calreticulin, suggesting that those signals might be associated with evading immune system recognition and thus averting senescent cells clearance.
Subject(s)
Antigens, CD1/metabolism , CD47 Antigen/metabolism , Cellular Senescence/physiology , Fibroblasts/metabolism , Histocompatibility Antigens Class I/metabolism , Lung/metabolism , Animals , Calbindin 2/metabolism , Cellular Senescence/drug effects , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Female , Fibroblasts/cytology , Hydrogen Peroxide/toxicity , Mice , Primary Cell CultureABSTRACT
BACKGROUND: The prognosis of advanced laryngeal cancer is unfavorable despite advances in multidisciplinary therapy. Dendritic cells (DCs) play a central role in antitumor immunity. Tumor-infiltrating CD1a+ DCs have been reported to be associated with clinical outcomes in carcinomas of various organs, but the clinical impact of CD1a+ DCs in laryngeal cancer remains to be unequivocally established. METHODS: We retrospectively analyzed the cases of 57 patients with Stage III or IV laryngeal cancer who underwent a total laryngectomy. Immunohistochemistry detection of CD1a, S100 and CD8 was performed on representative resected specimens. CD1a+ DCs, S100+ DCs and CD8+ cytotoxic T-lymphocytes (CTLs) were evaluated, and the cases divided into high and low groups according to the cut-off of the median values for each of these 3 parameters. RESULTS: Compared to the CD1a-low group, the CD1a-high group had more advanced cases and showed significantly worse disease-specific survival (DSS) (P = 0.008) and overall survival (OS) (P = 0.032). The analyses of S100 DCs and CD8+ CTLs revealed no significant impact on clinical outcomes. However, multivariate analysis revealed that infiltration of CD1a+ DCs was an independent unfavorable prognostic factor for both DSS (P = 0.009) and OS (P = 0.013). CONCLUSIONS: Our results demonstrated that the infiltration of CD1a+ DCs was associated with unfavorable clinical outcomes in patients with advanced laryngeal cancer who underwent a total laryngectomy as the initial treatment.
Subject(s)
Antigens, CD1/metabolism , Biomarkers, Tumor/analysis , CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Laryngeal Neoplasms/mortality , Laryngectomy/mortality , Lymphocytes, Tumor-Infiltrating/immunology , Aged , Female , Follow-Up Studies , Humans , Laryngeal Neoplasms/immunology , Laryngeal Neoplasms/pathology , Laryngeal Neoplasms/surgery , Male , Prognosis , Retrospective Studies , Survival RateABSTRACT
Acute leukemia relapsing after chemotherapy plus allogeneic hematopoietic stem cell transplantation can be treated with donor-derived T cells, but this is hampered by the need for donor/recipient MHC-matching and often results in graft-versus-host disease, prompting the search for new donor-unrestricted strategies targeting malignant cells. Leukemia blasts express CD1c antigen-presenting molecules, which are identical in all individuals and expressed only by mature leukocytes, and are recognized by T cell clones specific for the CD1c-restricted leukemia-associated methyl-lysophosphatidic acid (mLPA) lipid antigen. Here, we show that human T cells engineered to express an mLPA-specific TCR, target diverse CD1c-expressing leukemia blasts in vitro and significantly delay the progression of three models of leukemia xenograft in NSG mice, an effect that is boosted by mLPA-cellular immunization. These results highlight a strategy to redirect T cells against leukemia via transfer of a lipid-specific TCR that could be used across MHC barriers with reduced risk of graft-versus-host disease.
Subject(s)
Antigens, CD1/immunology , Glycoproteins/immunology , Leukemia/immunology , Lysophospholipids/immunology , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes/immunology , Tissue Donors , Animals , Antigen Presentation , Antigens, CD1/metabolism , Glycoproteins/metabolism , Humans , Immunotherapy, Adoptive , Leukemia/metabolism , Leukemia/therapy , Lymphocyte Activation , Mice , Receptors, Antigen, T-Cell/genetics , Receptors, Chimeric Antigen/genetics , Receptors, Chimeric Antigen/immunology , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND AND AIM: Vitiligo is a progressive, autoimmune, hypomelanotic acquired disorder of skin which is characterized by depigmentation. The initial immunological events of this diseases are still at enigma that includes breach of immune tolerance, and defect in antigen presentation. Hence, we aimed to explore role of Dendritic cells (DCs) and its associated cytokines in the pathogenesis of generalized vitiligo (GV) patients. METHODOLOGY: For this case-control study, 20 active patients and controls were enrolled. Phenotypic characterization of myeloid and plasmacytoid DCs (mDCs, pDCs) were done by flow-cytometry. Primary culture of DCs was done by monocyte differentiation supplemented with rIL-4 and rGM-CSF. Functional analysis DCs related cytokines and co-stimulatory molecules (CD80, CD40) was done by ELISA and qPCR respectively. Tissue localization of DCs was evaluated by immunohistochemistry. RESULT: The frequency of mDCs (0.3715% v/s 0.188%) and pDCs (0.2331% v/s 0.1156%) were elevated in patients as compared to controls. Circulatory level of IL-12, TNF-α were significantly higher whereas IFN-α was decreased in patients than controls. Similar results were obtained in the culture supernatants of patients. Relative mRNA expression profiling of co-stimulatory molecules (CD80, CD40) were found to be up regulated in patient's skin. Tissue localization of Langerhans cells (Langerin, CD1a+) were found to be significantly higher in patients. CONCLUSION: Elevated frequency of mDCs and pDCs along with elevated levels of IL-12, TNF-α and CD80, CD40 may contribute in defective antigen presentation of DCs. Altered pro-inflammatory and anti-inflammatory cytokines along with tissue localization of Langerhans cells might be involved in the pathogenesis of GV. These DCs associated cytokines can be explored as a therapeutic target in future.