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1.
Oncoimmunology ; 11(1): 2052640, 2022.
Article in English | MEDLINE | ID: mdl-35309733

ABSTRACT

Chronic inflammation and oncogenic pathway activation are key-contributing factors in colorectal cancer pathogenesis. However, colorectal intrinsic mechanisms linking these two factors in cancer development are poorly defined. Here, we show that intestinal epithelial cell (IEC)-specific deletion of Dot1l histone methyltransferase (Dot1lΔIEC ) reduced H3K79 dimethylation (H3K79me2) in IECs and inhibited intestinal tumor formation in ApcMin - and AOM-DSS-induced colorectal cancer models. IEC-Dot1l abrogation was accompanied by alleviative colorectal inflammation and reduced Wnt/ß-catenin signaling activation. Mechanistically, Dot1l deficiency resulted in an increase in Foxp3+RORϒ+ regulatory T (Treg) cells and a decrease in inflammatory Th17 and Th22 cells, thereby reducing local inflammation in the intestinal tumor microenvironment. Furthermore, Dot1l deficiency caused a reduction of H3K79me2 occupancies in the promoters of the Wnt/ß-catenin signaling genes, thereby diminishing Wnt/ß-catenin oncogenic signaling pathway activation in colorectal cancer cells. Clinically, high levels of tumor H3K79me2 were detected in patients with colorectal carcinomas as compared to adenomas, and negatively correlated with RORϒ+FOXP3+ Treg cells. Altogether, we conclude that DOT1L is an intrinsic molecular node connecting chronic immune activation and oncogenic signaling pathways in colorectal cancer. Our work suggests that targeting the DOT1L pathway may control colorectal carcinogenesis. Significance: IEC-intrinsic DOT1L controls T cell subset balance and key oncogenic pathway activation, impacting colorectal carcinogenesis.


Subject(s)
Colorectal Neoplasms , Histone-Lysine N-Methyltransferase , T-Lymphocyte Subsets , Carcinogenesis/metabolism , Colorectal Neoplasms/pathology , Forkhead Transcription Factors/metabolism , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Humans , Inflammation , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology , Tumor Microenvironment , Wnt Signaling Pathway , beta Catenin/genetics , beta Catenin/metabolism
2.
Front Immunol ; 12: 808964, 2021.
Article in English | MEDLINE | ID: mdl-35095898

ABSTRACT

The clinical success of immunotherapy has revolutionized the treatment of cancer patients, bringing renewed attention to tumor-infiltrating lymphocytes (TILs) of various cancer types. Immune checkpoint blockade is effective in patients with mismatched repair defects and high microsatellite instability (dMMR-MSI-H) in metastatic colorectal cancer (CRC), leading the FDA to accelerate the approval of two programmed cell death 1 (PD-1) blocking antibodies, pembrolizumab and nivolumab, for treatment of dMMR-MSI-H cancers. In contrast, patients with proficient mismatch repair and low levels of microsatellite stability or microsatellite instability (pMMR-MSI-L/MSS) typically have low tumor-infiltrating lymphocytes and have shown unsatisfied responses to the immune checkpoint inhibitor. Different TILs environments reflect different responses to immunotherapy, highlighting the complexity of the underlying tumor-immune interaction. Profiling of TILs fundamental Indication would shed light on the mechanisms of cancer-immune evasion, thus providing opportunities for the development of novel therapeutic strategies. In this review, we summarize phenotypic diversities of TILs and their connections with prognosis in CRC and provide insights into the subsets-specific nature of TILs with different MSI status. We also discuss current clinical immunotherapy approaches based on TILs as well as promising directions for future expansion, and highlight existing clinical data supporting its use.


Subject(s)
Colorectal Neoplasms/etiology , Colorectal Neoplasms/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Tumor Microenvironment , Animals , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , B-Lymphocyte Subsets/pathology , Biomarkers , Colorectal Neoplasms/pathology , Colorectal Neoplasms/therapy , Combined Modality Therapy/adverse effects , Combined Modality Therapy/methods , Disease Management , Disease Susceptibility , Humans , Immunity , Immunotherapy/adverse effects , Immunotherapy/methods , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology , Treatment Outcome , Tumor Microenvironment/immunology
3.
Int J Mol Sci ; 23(2)2022 Jan 13.
Article in English | MEDLINE | ID: mdl-35055013

ABSTRACT

Acute lymphoblastic leukaemia (ALL) is an aggressive haematological tumour driven by the malignant transformation and expansion of B-cell (B-ALL) or T-cell (T-ALL) progenitors. The evolution of T-ALL pathogenesis encompasses different master developmental pathways, including the main role played by Notch in cell fate choices during tissue differentiation. Recently, a growing body of evidence has highlighted epigenetic changes, particularly the altered expression of microRNAs (miRNAs), as a critical molecular mechanism to sustain T-ALL. The immune response is emerging as key factor in the complex multistep process of cancer but the role of miRNAs in anti-leukaemia response remains elusive. In this review we analyse the available literature on miRNAs as tuners of the immune response in T-ALL, focusing on their role in Natural Killer, T, T-regulatory and Myeloid-derived suppressor cells. A better understanding of this molecular crosstalk may provide the basis for the development of potential immunotherapeutic strategies in the leukemia field.


Subject(s)
Biomarkers, Tumor , Gene Expression Regulation, Leukemic , Immunomodulation/genetics , MicroRNAs/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/etiology , Animals , Disease Progression , Disease Susceptibility , Humans , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/therapy , RNA Interference , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology , Transcription, Genetic , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology
4.
Front Immunol ; 12: 696415, 2021.
Article in English | MEDLINE | ID: mdl-34987496

ABSTRACT

Disseminated infection with the high virulence strain of Mycobacterium avium 25291 leads to progressive thymic atrophy. We previously showed that M. avium-induced thymic atrophy results from increased glucocorticoid levels that synergize with nitric oxide (NO) produced by interferon gamma (IFNγ) activated macrophages. Where and how these mediators act is not understood. We hypothesized that IFNγ and NO promote thymic atrophy through their effects on bone marrow (BM) T cell precursors and T cell differentiation in the thymus. We show that M. avium infection cause a reduction in the percentage and number of common lymphoid progenitors (CLP). Additionally, BM precursors from infected mice show an overall impaired ability to reconstitute thymi of RAGKO mice, in part due to IFNγ. Thymi from infected mice present an IFNγ and NO-driven inflammation. When transplanted under the kidney capsule of uninfected mice, thymi from infected mice are unable to sustain T cell differentiation. Finally, we observed increased thymocyte death via apoptosis after infection, independent of both IFNγ and iNOS; and a decrease on active caspase-3 positive thymocytes, which is not observed in the absence of iNOS expression. Together our data suggests that M. avium-induced thymic atrophy results from a combination of defects mediated by IFNγ and NO, including alterations in the BM T cell precursors, the thymic structure and the thymocyte differentiation.


Subject(s)
Bone Marrow/pathology , Interferon-gamma/physiology , Lymphoid Progenitor Cells/pathology , Nitric Oxide Synthase Type II/physiology , Thymus Gland/pathology , Tuberculosis/pathology , Animals , Apoptosis , Atrophy , Bone Marrow Transplantation , Cell Differentiation , DNA-Binding Proteins/deficiency , Female , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Mycobacterium avium , Nitric Oxide/physiology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/pathology , Thymocytes/pathology , Thymus Gland/transplantation , Tuberculosis/immunology
5.
Front Immunol ; 12: 808527, 2021.
Article in English | MEDLINE | ID: mdl-34970279

ABSTRACT

Yearly administration of influenza vaccines is our best available tool for controlling influenza virus spread. However, both practical and immunological factors sometimes result in sub-optimal vaccine efficacy. The call for improved, or even universal, influenza vaccines within the field has led to development of pre-clinical and clinical vaccine candidates that aim to address limitations of current influenza vaccine approaches. Here, we consider the route of immunization as a critical factor in eliciting tissue resident memory (Trm) populations that are not a target of current licensed intramuscular vaccines. Intranasal vaccination has the potential to boost tissue resident B and T cell populations that reside within specific niches of the upper and lower respiratory tract. Within these niches, Trm cells are poised to respond rapidly to pathogen re-encounter by nature of their anatomic localization and their ability to rapidly deliver anti-pathogen effector functions. Unique features of mucosal immunity in the upper and lower respiratory tracts suggest that antigen localized to these regions is required for the elicitation of protective B and T cell immunity at these sites and will need to be considered as an important attribute of a rationally designed intranasal vaccine. Finally, we discuss outstanding questions and areas of future inquiry in the field of lung mucosal immunity.


Subject(s)
Immunity, Mucosal , Lung/immunology , Respiratory Mucosa/immunology , Vaccines/immunology , Administration, Intranasal , Animals , Antibodies, Viral/immunology , Humans , Immunization , Immunologic Memory , Influenza Vaccines/administration & dosage , Influenza Vaccines/immunology , Lung/metabolism , Respiratory Mucosa/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology , Vaccines/administration & dosage
6.
Sci Rep ; 11(1): 23819, 2021 12 10.
Article in English | MEDLINE | ID: mdl-34893671

ABSTRACT

Neurotropic viruses target the brain and contribute to neurologic diseases. C-type lectin receptors (CLRs) are pattern recognition receptors that recognize carbohydrate structures on endogenous molecules and pathogens. The myeloid CLR dendritic cell immunoreceptor (DCIR) is expressed by antigen presenting cells and mediates inhibitory intracellular signalling. To investigate the effect of DCIR on neurotropic virus infection, mice were infected experimentally with Theiler's murine encephalomyelitis virus (TMEV). Brain tissue of TMEV-infected C57BL/6 mice and DCIR-/- mice were analysed by histology, immunohistochemistry and RT-qPCR, and spleen tissue by flow cytometry. To determine the impact of DCIR deficiency on T cell responses upon TMEV infection in vitro, antigen presentation assays were utilised. Genetic DCIR ablation in C57BL/6 mice was associated with an ameliorated hippocampal integrity together with reduced cerebral cytokine responses and reduced TMEV loads in the brain. Additionally, absence of DCIR favoured increased peripheral cytotoxic CD8+ T cell responses following TMEV infection. Co-culture experiments revealed that DCIR deficiency enhances the activation of antigen-specific CD8+ T cells by virus-exposed dendritic cells (DCs), indicated by increased release of interleukin-2 and interferon-γ. Results suggest that DCIR deficiency has a supportive influence on antiviral immune mechanisms, facilitating virus control in the brain and ameliorates neuropathology during acute neurotropic virus infection.


Subject(s)
Cardiovirus Infections/virology , Hippocampus/metabolism , Hippocampus/virology , Lectins, C-Type/metabolism , Theilovirus/physiology , Animals , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , Biomarkers , Biopsy , Cytokines/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Disease Models, Animal , Disease Susceptibility , Hippocampus/pathology , Immunohistochemistry , Immunomodulation , Lectins, C-Type/genetics , Mice , Mice, Knockout , /metabolism , /virology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology , Viral Load
7.
Sci Rep ; 11(1): 22242, 2021 11 15.
Article in English | MEDLINE | ID: mdl-34782633

ABSTRACT

Talimogene laherparepvec (T-VEC) is an immunotherapy that generates local tumor lysis and systemic antitumor immune response. We studied the efficacy of intratumoral administration of T-VEC as monotherapy for inoperable locoregional recurrence of breast cancer. T-VEC was injected intratumorally at 106 PFU/mL on day 1 (cycle 1), 108 PFU/mL on day 22 (cycle 2), and 108 PFU/mL every 2 weeks thereafter (cycles ≥ 3). Nine patients were enrolled, 6 with only locoregional disease and 3 with both locoregional and distant disease. No patient completed the planned 10 cycles or achieved complete or partial response. The median number of cycles administered was 4 (range, 3-8). Seven patients withdrew prematurely because of uncontrolled disease progression, 1 withdrew after cycle 3 because of fatigue, and 1 withdrew after cycle 4 for reasons unrelated to study treatment. Median progression-free survival and overall survival were 77 days (95% CI, 63-NA) and 361 days (95% CI, 240-NA). Two patients received 8 cycles with clinically stable disease as the best response. The most common grade 2 or higher adverse event was injection site reaction (n = 7, 78%). Future studies could examine whether combining intratumoral T-VEC with concurrent systemic therapy produces better outcomes.


Subject(s)
Biological Products/therapeutic use , Breast Neoplasms/therapy , Genetic Therapy , Oncolytic Virotherapy , Adult , Aged , Biological Products/administration & dosage , Biological Products/adverse effects , Biomarkers , Breast Neoplasms/diagnosis , Breast Neoplasms/etiology , Breast Neoplasms/mortality , Combined Modality Therapy , Female , Genetic Therapy/methods , Herpesvirus 1, Human , Humans , Immunophenotyping , Immunotherapy , Lymphocyte Count , Middle Aged , Oncolytic Virotherapy/adverse effects , Oncolytic Virotherapy/methods , Prognosis , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology , Treatment Outcome
8.
EBioMedicine ; 73: 103664, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34740105

ABSTRACT

BACKGROUND: Although T cell abundance in solid tumours is associated with better outcomes, it also correlates with a stroma-mediated source of immune suppression driven by TGFß1 and poor overall survival. Whether this also is observed in non-small cell lung cancer (NSCLC) is unknown. METHODS: We utilized molecular analysis of The Cancer Genome Atlas (TCGA) NSLCC cohort to correlate immune activation (IA) gene expression and extracellular matrix/stromal (ECM/stromal) gene expression with patient survival. In an independent cohort of NSCLC samples, we used flow cytometry to identify mesenchymal subsets and ex vivo functional studies to characterize their immune regulatory function. FINDINGS: We observed a high enrichment in a core set of genes defining an IA gene expression signature in NSCLC across TCGA Pan-cancer cohort. High IA signature score correlates with enrichment of ECM/stromal gene signature across TCGA NSCLC datasets. Importantly, a higher ratio of ECM/stromal to IA gene signature score was associated with shorter overall survival. In tumours resected from a separate cohort of NSCLC patients, we identified CD90+CD73+ peritumoral cells that were enriched in the ECM/stromal gene signature, which was amplified by TGFß1. IFNγ and TNFα-primed peritumoral CD90+CD73+ cells upregulate immune checkpoint molecules PD-L1 and IDO1 and secrete an array of cytokines/chemokines including TGFß1. Finally, immune primed peritumoral CD90+CD73+ cells suppress T cell function, which was relieved following combined blockade of PD-L1 and TGFß1 with IDO1 inhibition but not PD-L1 or anti-CD73 alone. INTERPRETATION: Our findings suggest that targeting PD-L1 together with independent biological features of the stroma may enhance host antitumor immunity in NSCLC. FUNDING: LW and HY are supported by a 4-year China Scholarship Council award. This work was funded, in part, by a grant from the Cancer League of Bern, Switzerland to SRRH. Laser scanning microscopy imaging was funded by the R'Equip grant from the Swiss National Science Foundation Nr. 316030_145003.


Subject(s)
5'-Nucleotidase/metabolism , Carcinoma, Non-Small-Cell Lung/etiology , Carcinoma, Non-Small-Cell Lung/metabolism , Immunomodulation , Lung Neoplasms/etiology , Lung Neoplasms/metabolism , Thy-1 Antigens/metabolism , Tumor Microenvironment , Biomarkers , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/pathology , Computational Biology , Databases, Genetic , Extracellular Matrix , GPI-Linked Proteins/metabolism , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Immunomodulation/genetics , Immunophenotyping , Lung Neoplasms/pathology , Models, Biological , Stromal Cells/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology , Transcriptome , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology
9.
Front Immunol ; 12: 719954, 2021.
Article in English | MEDLINE | ID: mdl-34721383

ABSTRACT

The constant exposure of the liver to gut derived foreign antigens has resulted in this organ attaining unique immunological characteristics, however it remains susceptible to immune mediated injury. Our understanding of this type of injury, in both the native and transplanted liver, has improved significantly in recent decades. This includes a greater awareness of the tolerance inducing CD4+ CD25+ CD127low T-cell lineage with the transcription factor FoxP3, known as regulatory T-Cells (Tregs). These cells comprise 5-10% of CD4+ T cells and are known to function as an immunological "braking" mechanism, thereby preventing immune mediated tissue damage. Therapies that aim to increase Treg frequency and function have proved beneficial in the setting of both autoimmune diseases and solid organ transplantations. The safety and efficacy of Treg therapy in liver disease is an area of intense research at present and has huge potential. Due to these cells possessing significant plasticity, and the potential for conversion towards a T-helper 1 (Th1) and 17 (Th17) subsets in the hepatic microenvironment, it is pre-requisite to modify the microenvironment to a Treg favourable atmosphere to maintain these cells' function. In addition, implementation of therapies that effectively increase Treg functional activity in the liver may result in the suppression of immune responses and will hinder those that destroy tumour cells. Thus, fine adjustment is crucial to achieve this immunological balance. This review will describe the hepatic microenvironment with relevance to Treg function, and the role these cells have in both native diseased and transplanted livers.


Subject(s)
Immunotherapy/methods , Liver Diseases/therapy , Liver Transplantation , T-Lymphocytes, Regulatory/immunology , Animals , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/immunology , Cell Transformation, Neoplastic/metabolism , Cellular Microenvironment/immunology , Chronic Disease , Disease Management , Disease Susceptibility/etiology , Disease Susceptibility/metabolism , Humans , Immunomodulation , Immunotherapy/adverse effects , Liver Diseases/diagnosis , Liver Diseases/etiology , Liver Diseases/metabolism , Liver Transplantation/adverse effects , Liver Transplantation/methods , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/metabolism , Treatment Outcome
10.
Infect Immun ; 90(1): e0045321, 2022 01 25.
Article in English | MEDLINE | ID: mdl-34724387

ABSTRACT

Chlamydia trachomatis is a leading infectious cause of infertility in women due to its induction of lasting pathology such as hydrosalpinx. Chlamydia muridarum induces mouse hydrosalpinx because C. muridarum can both invade tubal epithelia directly (as a first hit) and induce lymphocytes to promote hydrosalpinx indirectly (as a second hit). In the current study, a critical role of CD8+ T cells in chlamydial induction of hydrosalpinx was validated in both wild type C57BL/6J mice and OT1 transgenic mice. OT1 mice failed to develop hydrosalpinx partially due to the failure of their lymphocytes to recognize chlamydial antigens. CD8+ T cells from naive C57BL/6J mice rescued the ability of recipient OT1 mice to develop hydrosalpinx when naive CD8+ T cells were transferred at the time of infection with Chlamydia. However, when the transfer was delayed for 2 weeks or longer after the Chlamydia infection, naive CD8+ T cells no longer promoted hydrosalpinx. Nevertheless, CD8+ T cells from mice immunized against Chlamydia still promoted significant hydrosalpinx in the recipient OT1 mice even when the transfer was delayed for 3 weeks. Thus, CD8+ T cells must be primed within 2 weeks after Chlamydia infection to be pathogenic, but, once primed, they can promote hydrosalpinx for >3 weeks. However, Chlamydia-primed CD4+ T cells failed to promote chlamydial induction of pathology in OT1 mice. This study optimized an OT1 mouse-based model for revealing the pathogenic mechanisms of Chlamydia-specific CD8+ T cells.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Chlamydia Infections/immunology , Chlamydia Infections/metabolism , Chlamydia Infections/microbiology , Chlamydia muridarum/immunology , Animals , Antigens, Bacterial/immunology , Biopsy , Disease Models, Animal , Disease Susceptibility , Female , Host-Pathogen Interactions/immunology , Mice , Salpingitis/etiology , Salpingitis/metabolism , Salpingitis/pathology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology
11.
Sci Rep ; 11(1): 19629, 2021 10 04.
Article in English | MEDLINE | ID: mdl-34608214

ABSTRACT

Detailed analysis of the cells that infiltrate lesional skin cannot be performed in skin biopsy specimens using immunohistochemistry or cell separation techniques because enzyme treatments applied during the isolation step can destroy small amounts of protein and minor cell populations in the biopsy specimen. Here, we describe a method for isolating T cells from drops of whole blood obtained from lesions during skin biopsy in patients with cutaneous T-cell lymphoma. Lesional blood is assumed to contain lesional resident cells, cells from capillary vessels, and blood overflowing from capillary vessels into the lesion area. The lesional blood showed substantial increases in distinct cell populations, chemokines, and the expression of various genes. The proportion of CD8+CD45RO+ T cells in the lesional blood negatively correlated with the modified severity-weighted assessment tool scores. CD4+CD45RO+ T cells in the lesional blood expressed genes associated with the development of cancer and progression of cutaneous T-cell lymphoma. In addition, CD8+CD45RO+ T cells in lesional blood had unique T-cell receptor repertoires in lesions of each stage. Assessment of lesional blood drops might provide new insight into the pathogenesis of mycosis fungoides and facilitate evaluation of the treatment efficacy for mycosis fungoides as well as other skin inflammatory diseases.


Subject(s)
Biomarkers, Tumor , Lymphoma, T-Cell, Cutaneous/blood , Lymphoma, T-Cell, Cutaneous/etiology , Tumor Microenvironment/immunology , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/blood , Disease Management , Disease Susceptibility , Female , Humans , Immunohistochemistry , Immunophenotyping , Lymphocyte Count , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphocytes, Tumor-Infiltrating/pathology , Lymphoma, T-Cell, Cutaneous/diagnosis , Male , Middle Aged , Neoplasm Staging , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology
12.
J Immunol Res ; 2021: 9752139, 2021.
Article in English | MEDLINE | ID: mdl-34414243

ABSTRACT

Uterine sensitization-associated gene-1 (USAG-1), originally identified as a secretory protein preferentially expressed in the sensitized rat endometrium, has been determined to modulate bone morphogenetic protein (BMP) and Wnt expression to play important roles in kidney disease. USAG-1 affects the progression of acute and chronic kidney damage and the recovery of allograft kidney function by regulating the BMP and Wnt signaling pathways. Moreover, USAG-1 has been found to be involved in the process of T cell immune response, and its ability to inhibit germinal center activity and reduce humoral immunity is of great significance for the treatment of autoimmune nephropathy and antibody-mediated rejection (AMR) after renal transplantation. This article summarizes the many advances made regarding the roles of USAG-1 in the progression of kidney disease and outlines potential treatments.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Biomarkers , Disease Susceptibility , Kidney Diseases/etiology , Kidney Diseases/metabolism , Animals , Bone Morphogenetic Protein 7/antagonists & inhibitors , Bone Morphogenetic Protein 7/metabolism , Disease Progression , Disease Susceptibility/immunology , Gene Expression Regulation , Humans , Kidney Diseases/pathology , Kidney Tubules/metabolism , Kidney Tubules/pathology , Signal Transduction , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology
13.
J Endocrinol Invest ; 45(2): 413-423, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34392500

ABSTRACT

PURPOSE: Subjects with obesity may exhibit an increase in serum TSH concentrations. Several mechanisms have been proposed to explain this association, including the presence of a compensatory mechanism to counterbalance an accelerated turnover of thyroid hormones in subjects with obesity. This study aimed at evaluating whether the thyroids of subjects with obesity differs from those of normal-weight individuals regarding histology and gene expression profiling. METHODS: Ninety-eight patients were selected among those scheduled for thyroidectomy. At histology, thyroid tissue samples were investigated for the presence of adipocytes and/or lymphocyte infiltration. In a subset of patients, the expression at mRNA level of several genes involved in metabolic pathways and immune cell-related mechanisms was quantified by NanoString Technology. RESULTS: The presence of adipose cells was documented in thyroid specimens from 40% normal weight, 52.9% overweight and 73.5% patients with obesity. The number of infiltrating adipocytes was greater in specimens of patients with overweight or obesity compared to normal weight. The lymphocytes common antigen (CD45) and mast cell (MC) scores, and the number of CD3+ and CD8+ lymphocytes were higher in patients with overweight and obesity than in normal-weight subjects. Several genes involved in metabolic pathways were differently expressed in patients with overweight or obesity compared to normal weight, with upregulation of Leptin receptor and downregulation of Fatty Acid-Binding Protein 5. CONCLUSIONS: Increased BMI is associated with adipocyte and lymphocyte infiltration of the thyroid, not related to an autoimmune process, which might affect thyroid function in subjects with obesity. A differential gene expression profiling of metabolic and immune pathways in thyroid tissues of patients with obesity was also observed.


Subject(s)
Fatty Acid-Binding Proteins/analysis , Obesity , Receptors, Leptin/analysis , T-Lymphocyte Subsets , Thyroid Gland , Thyroid Hormones/metabolism , Adipocytes/immunology , Adipocytes/pathology , Body Mass Index , Female , Gene Expression Profiling/methods , Humans , Immunity, Cellular , Male , Metabolic Networks and Pathways , Middle Aged , Obesity/diagnosis , Obesity/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/pathology , Thyroid Gland/metabolism , Thyroid Gland/pathology
14.
Front Immunol ; 12: 713132, 2021.
Article in English | MEDLINE | ID: mdl-34386013

ABSTRACT

Senescent T cells have been described during aging, chronic infections, and cancer; however, a comprehensive study of the phenotype, function, and transcriptional program of this T cell population in breast cancer (BC) patients is missing. Compared to healthy donors (HDs), BC patients exhibit an accumulation of KLRG-1+CD57+ CD4+ and CD8+ T cells in peripheral blood. These T cells infiltrate tumors and tumor-draining lymph nodes. KLRG-1+CD57+ CD4+ and CD8+ T cells from BC patients and HDs exhibit features of senescence, and despite their inhibitory receptor expression, they produce more effector cytokines and exhibit higher expression of Perforin, Granzyme B, and CD107a than non-senescent subsets. When compared to blood counterparts, tumor-infiltrating senescent CD4+ T cells show similar surface phenotype but reduced cytokine production. Transcriptional profiling of senescent CD4+ T cells from the peripheral blood of BC patients reveals enrichment in genes associated with NK or CD8+-mediated cytotoxicity, TCR-mediated stimulation, and cell exhaustion compared to non-senescent T cells. Comparison of the transcriptional profile of senescent CD4+ T cells from peripheral blood of BC patients with those of HDs highlighted marked similarities but also relevant differences. Senescent CD4+ T cells from BC patients show enrichment in T-cell signaling, processes involved in DNA replication, p53 pathways, oncogene-induced senescence, among others compared to their counterparts in HDs. High gene expression of CD4, KLRG-1, and B3GAT1 (CD57), which correlates with increased overall survival for BC patients, underscores the usefulness of the evaluation of the frequency of senescent CD4+ T cells as a biomarker in the follow-up of patients.


Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cellular Senescence , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Breast Neoplasms/etiology , CD57 Antigens/metabolism , Case-Control Studies , Cellular Senescence/genetics , Cellular Senescence/immunology , Cytotoxicity, Immunologic , Female , Gene Expression Profiling , Humans , Immunophenotyping , Lectins, C-Type/metabolism , Lymphocyte Count , Lymphocytes, Tumor-Infiltrating/pathology , Receptors, Immunologic/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology
15.
J Mol Endocrinol ; 67(4): 173-188, 2021 09 09.
Article in English | MEDLINE | ID: mdl-34382943

ABSTRACT

Epidemiological studies inversely associate BMI with breast cancer risk in premenopausal women, but the pathophysiological linkage remains ill-defined. Despite the documented relevance of the 'local' environment to breast cancer progression and the well-accepted differences in transcriptome and metabolic properties of anatomically distinct fat depots, specific breast adipose contributions to the proliferative potential of non-diseased breast glandular compartment are not fully understood. To address early breast cancer causation in the context of obesity status, we compared the cellular and molecular phenotypes of breast adipose and matched breast glandular tissue from premenopausal non-obese (mean BMI = 27 kg/m2) and obese (mean BMI = 44 kg/m2) women. Breast adipose from obese women showed higher expression levels of adipogenic, pro-inflammatory, and estrogen synthetic genes than from non-obese women. Obese breast glandular tissue displayed lower proliferation and inflammatory status and higher expression of anti-proliferative/pro-senescence biomarkers TP53 and p21 than from non-obese women. Transcript levels for T-cell receptor and co-receptors CD3 and CD4 were higher in breast adipose of obese cohorts, coincident with elevated adipose interleukin 10 (IL10) and FOXP3 gene expression. In human breast epithelial cell lines MCF10A and HMEC, recombinant human IL10 reduced cell viability and CCND1 transcript levels, increased those of TP53 and p21, and promoted (MCF10A) apoptosis. Our findings suggest that breast adipose-associated IL10 may mediate paracrine interactions between non-diseased breast adipose and breast glandular compartments and highlight how breast adipose may program the local inflammatory milieu, partly by recruiting FOXP3+ T regulatory cells, to influence premenopausal breast cancer risk.


Subject(s)
Adipose Tissue/metabolism , Breast/metabolism , Epithelium/metabolism , Interleukin-10/metabolism , Phenotype , Premenopause/metabolism , Adipocytes/immunology , Adipocytes/metabolism , Adiposity , Adult , Biomarkers , Breast/pathology , Breast Neoplasms/etiology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Cytokines/genetics , Cytokines/metabolism , Female , Gene Expression , Gonadal Steroid Hormones/blood , Gonadal Steroid Hormones/metabolism , Humans , Immunohistochemistry , Inflammation Mediators/metabolism , Middle Aged , Models, Biological , Obesity/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology , Telomere/genetics , Telomere/metabolism , Young Adult
16.
Mol Nutr Food Res ; 65(19): e2100346, 2021 10.
Article in English | MEDLINE | ID: mdl-34369649

ABSTRACT

INTRODUCTION: Pectins have anti-inflammatory properties on intestinal immunity through direct interactions on Toll-like receptors (TLRs) in the small intestine or via stimulating microbiota-dependent effects in the large intestine. Both the degree of methyl-esterification (DM) and the distribution of methyl-esters (degree of blockiness; DB) of pectins contribute to this influence on immunity, but whether and how the DB impacts immunity through microbiota-dependent effects in the large intestine is unknown. Therefore, this study tests pectins that structurally differ in DB in a mouse model with Citrobacter rodentium induced colitis and studies the impact on the intestinal microbiota composition and associated attenuation of inflammation. METHODS AND RESULTS: Both low and high DB pectins induce a more rich and diverse microbiota composition. These pectins also lower the bacterial load of C. rodentium in cecal digesta. Through these effects, both low and high DB pectins attenuate C. rodentium induced colitis resulting in reduced intestinal damage, reduced numbers of Th1-cells, which are increased in case of C. rodentium induced colitis, and reduced levels of GATA3+ Tregs, which are related to tissue inflammation. CONCLUSION: Pectins prevent C. rodentium induced colonic inflammation by lowering the C. rodentium load in the caecum independently of the DB.


Subject(s)
Colitis/drug therapy , Enterobacteriaceae Infections/drug therapy , Pectins/chemistry , Pectins/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cecum/drug effects , Cecum/metabolism , Citrobacter rodentium/pathogenicity , Citrus sinensis/chemistry , Colitis/microbiology , Colitis/pathology , Cytokines/metabolism , Enterobacteriaceae Infections/pathology , Esters/chemistry , Female , Gastrointestinal Microbiome/drug effects , Gastrointestinal Microbiome/genetics , Mice, Inbred C57BL , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/pathology
17.
Technol Cancer Res Treat ; 20: 15330338211034265, 2021.
Article in English | MEDLINE | ID: mdl-34323154

ABSTRACT

OBJECTIVE: To evaluate the prognostic value of tumor infiltrating lymphocytes (TILs) in nasopharyngeal carcinoma (NPC) patients. METHOD: Meta-analysis was performed on eligible studies that was identified by systematic searching of Google scholar, MEDLINE, CNKI, Scopus, PubMed, PMC, Embase and Web of Science databases. The study protocol was registered in International Platform of Registered Systematic Review and Meta-Analysis Protocols-INPLASY (registration number: INPLASY202160014). Databases were searched from inception to January 20, 2020 to identify eligible studies. Those studies that evaluated survival in the form of hazard ratio (HR) in TILs of NPC patients was analyzed. All statistical analysis was performed by using STATA version 16.0 software. RESULT: Fourteen studies with a total of 3025 patients was analyzed. The pooled result showed that high TILs was significantly associated with favorable overall survival (OS) (HR = 0.55; 95%CI = 0.39-0.77; P = 0.001) and disease free survival (DFS) (HR = 0.60; 95%CI = 0.44-0.81; P = 0.04). Interestingly, high intratumoral TILs had relatively better OS (HR = 0.45; 95%CI = 0.35-0.58; P = 0.006) than stromal TILs (HR = 0.59; 95%CI = 0.36-0.97; P = 0.03). Moreover, an increased level of CD4+ cells infiltration was correlated with favorable OS (HR = 0.4; 95%CI = 0.18-0.85; P = 0.01). CD3+, CD8+ and FoxP3+ lymphocyte's better prognosis was not statistically significant for OS (P = 0.09; P = 0.07; P = 0.52) and for DFS (P = 0.13; P = 0.29) respectively. However, subgroup analysis of intratumoral CD3+ (HR = 0.48; 95%CI = 0.33-0.70; P = 0.05) and intratumoral CD8+ (HR = 0.32; 95%CI = 0.16-0.62; P = 0.001) was significantly associated with improved OS, but not significant in stromal CD3+ (HR = 0.66; 95%CI = 0.20-2.20; P = 0.62). CONCLUSION: TILs were variably correlated with better prognosis depending on their microanatomic location and subset of TILs in NPC patients. CD4+, intratumoral CD3+ and intratumoral CD8+ lymphocytes could predict favorable patient outcome which suggest that their role in mediating antitumor immune response could potentially be exploited in the treatment of NPC patients. Future large study on the prognostic value of microanatomic location of TILs is needed for confirmation.


Subject(s)
Lymphocytes, Tumor-Infiltrating/pathology , Nasopharyngeal Carcinoma/mortality , Nasopharyngeal Carcinoma/pathology , Tumor Microenvironment , Disease Susceptibility , Humans , Immunophenotyping , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Nasopharyngeal Carcinoma/immunology , Prognosis , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology , Tumor Microenvironment/immunology
18.
Immunol Res ; 69(5): 398-414, 2021 10.
Article in English | MEDLINE | ID: mdl-34302619

ABSTRACT

Th17 and Treg cells play an important role in regulating tissue inflammation and maintaining the stability of the immune system. They regulate inflammatory responses, participate in the occurrence and development of autoimmune diseases and tumors, and determine the disease progress. Malignant tumor is one of the diseases with the highest mortality rate in the world. However, the efficacy of traditional treatment is limited, so it is necessary to find safe and efficient treatment methods. Studies have shown that the balance of Th17/Treg cells plays a critical role in tumor progression. In this paper, we review the antitumor and tumor-suppressing effects of Th17/Treg cells, and new strategies for tumor therapy, combined with new research hotspots such as immune checkpoint therapy, miRNA-related gene therapy, and metabolic pathway regulation of Th17/Treg cell differentiation and tumor generation. The synergistic therapy is expected to be widely used in the future clinical practice, providing a new choice for the prevention and treatment of malignant tumors.


Subject(s)
Disease Susceptibility , Neoplasms/etiology , Neoplasms/therapy , T-Lymphocytes, Regulatory/immunology , Th17 Cells/immunology , Tumor Microenvironment/immunology , Animals , Biomarkers , Cell Communication/genetics , Cell Communication/immunology , Cell Plasticity/immunology , Combined Modality Therapy , Disease Management , Disease Susceptibility/immunology , Humans , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphocytes, Tumor-Infiltrating/pathology , Neoplasms/diagnosis , Neoplasms/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology , T-Lymphocytes, Regulatory/metabolism , Th17 Cells/metabolism , Treatment Outcome
19.
Clin Immunol ; 229: 108797, 2021 08.
Article in English | MEDLINE | ID: mdl-34273585

ABSTRACT

The global obesity epidemic is contributing to increased prevalence of diseases fuelled by chronic inflammation, including cancer. Oesophageal adenocarcinoma (OAC) is an obesity-associated malignancy with increasing prevalence, dismal prognosis, and severely dysregulated immune processes. We previously reported that αß T cells migrate to omentum and liver in OAC and contribute to inflammation in these tissues. Here, we assessed the tissue distribution and phenotype of gamma/delta (γδ) T cells in the blood, omentum, liver and tumour of OAC patients. Our data show that the Vδ1 and Vδ3 subsets of γδ T cells are most prevalent in omentum and liver of OAC patients. Furthermore, γδ T cells are predominantly pro-inflammatory in these tissues, and co-express IFN-γ and IL-17. Moreover, γδ T cells exhibit cytotoxic capabilities in OAC omentum and liver. This study provides the first indication that γδ T cells contribute to obesity-associated inflammation in OAC and might be exploited therapeutically.


Subject(s)
Adenocarcinoma/immunology , Esophageal Neoplasms/immunology , Receptors, Antigen, T-Cell, gamma-delta/metabolism , T-Lymphocyte Subsets/immunology , Adenocarcinoma/etiology , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Cell Degranulation , Esophageal Neoplasms/etiology , Esophageal Neoplasms/pathology , Female , Humans , Immunophenotyping , Inflammation/complications , Interferon-gamma/metabolism , Interleukin-17/metabolism , Liver/immunology , Liver/pathology , Lysosomal-Associated Membrane Protein 1/metabolism , Male , Middle Aged , Obesity/complications , Omentum/immunology , Omentum/pathology , Receptors, CCR6/metabolism , T-Lymphocyte Subsets/pathology , T-Lymphocyte Subsets/physiology , Tissue Distribution
20.
Sci Rep ; 11(1): 14047, 2021 07 07.
Article in English | MEDLINE | ID: mdl-34234274

ABSTRACT

The Apelin/APJ signalling pathway, involved in multiple physiological and pathological processes, has been attracting increasing interest recently. In our previous study, Apelin overexpression in colon26 tumor cells suppressed tumor growth by inducing vascular maturation. Here, we found that MC38 and LLC tumor growth were greater in the absence of Apelin than in wild-type (WT) mice, suggesting that Apelin acts as a tumor suppressor. Consistent with this, treating WT mice with [Pyr1]Apelin-13 inhibited tumor growth. In MC38 tumors, only endothelial cells (ECs) strongly express APJ, a cognate receptor for Apelin, indicating that EC-derived Apelin might regulate tumor formation in an autocrine manner. Comparing with WT mice, larger numbers of vessels with narrower diameters were observed in tumors of Apelin knockout mice and lack of Apelin enhanced tumor hypoxia. Investigating immune cells in the tumor revealed that [Pyr1]Apelin-13 infusion induced the accumulation of CD8+ and CD4+ T cells in central areas. Moreover, RNA-sequencing analysis showed that Apelin induces chemokine CCL8 expression in ECs. Thus, enhancing anti-tumor immunity might be one of the mechanisms by which Apelin is involved in tumor growth. Our result indicated that increased CCL8 expression might induce CD8 + T cells infiltration into tumor and tumor inhibition.


Subject(s)
Apelin/metabolism , Chemotaxis, Leukocyte/genetics , Endothelial Cells/metabolism , Neoplasms/etiology , Neoplasms/metabolism , Animals , Apelin/genetics , Apelin Receptors/genetics , Apelin Receptors/metabolism , Cell Line, Tumor , Cell Proliferation , Chemokine CCL8/biosynthesis , Chemotaxis, Leukocyte/immunology , Disease Models, Animal , Humans , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphocytes, Tumor-Infiltrating/pathology , Mice , Mice, Knockout , Neoplasms/pathology , Protein Binding , Signal Transduction , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology , Tumor Microenvironment
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