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Journal of Clinical Medicine Dec 2022Immune checkpoint inhibitors (ICI) targeting programmed death 1 (PD-1), its ligand (PD-L1), or cytotoxic T-lymphocyte antigen 4 (CTLA-4) have shown promising results... (Review)
Review
Immune checkpoint inhibitors (ICI) targeting programmed death 1 (PD-1), its ligand (PD-L1), or cytotoxic T-lymphocyte antigen 4 (CTLA-4) have shown promising results against multiple cancers, where they reactivate exhausted T cells primed to eliminate tumor cells. ICI therapies have been particularly successful in hypermutated cancers infiltrated with lymphocytes. However, resistance may appear in tumors evading the immune system through alternative mechanisms than the PD-1/PD-L1 or CTLA-4 pathways. A systematic pan-cancer literature search was conducted to examine the association between alternative immune evasion mechanisms via the antigen presentation machinery (APM) and resistance towards ICI treatments targeting PD-1 (pembrolizumab and nivolumab), PD-L1 (durvalumab, avelumab, and atezolizumab), and CTLA-4 (ipilimumab). The APM proteins included the human leucocyte antigen (HLA) class I, its subunit beta-2 microglobulin (B2M), the transporter associated with antigen processing (TAP) 1, TAP2, and the NOD-like receptor family CARD domain containing 5 (NLRC5). In total, 18 cohort studies (including 21 original study cohorts) containing 966 eligible patients and 9 case studies including 12 patients were reviewed. Defects in the APM significantly predicted poor clinical benefit with an odds ratio (OR) of 0.39 (95% CI 0.24−0.63, p < 0.001). The effect was non-significant, when considering complete and partial responses only (OR = 0.52, 95% CI 0.18−1.47, p = 0.216). In summary, the APM contains important targets for tumorigenic alterations which may explain insensitivity towards ICI therapy.
PubMed: 36615128
DOI: 10.3390/jcm12010329 -
International Journal of Molecular... Dec 2020Natural killer (NK) cells, as members of the innate immune system, and natural killer T (NKT) cells, bridging innate and adaptive immunity, play a prominent role in...
Natural killer (NK) cells, as members of the innate immune system, and natural killer T (NKT) cells, bridging innate and adaptive immunity, play a prominent role in chronic inflammatory diseases and cancerogenesis, yet have scarcely been examined in oral diseases. Therefore, systematic research on the latest literature focusing on NK/NKT cell-mediated mechanisms in periodontal disease, including the time period 1988-2020, was carried out in MEDLINE (PubMed) using a predetermined search strategy, with a final selection of 25 studies. The results showed that NK cells tend to have rather proinflammatory influences via cytokine production, cytotoxic effects, dendritic-cell-crosstalk, and autoimmune reactions, while contrarily, NKT cell-mediated mechanisms were proinflammatory and immunoregulatory, ranging from protective effects via B-cell-regulation, specific antibody production, and the suppression of autoimmunity to destructive effects via cytokine production, dendritic-cell-crosstalk, and T-/B-cell interactions. Since NK cells seem to have a proinflammatory role in periodontitis, further research should focus on the proinflammatory and immunoregulatory properties of NKT cells in order to create, in addition to antibacterial strategies in dental inflammatory disease, novel anti-inflammatory therapeutic approaches modulating host immunity towards dental health.
Topics: Animals; Humans; Immunity, Innate; Killer Cells, Natural; Natural Killer T-Cells; Periodontal Diseases
PubMed: 33371393
DOI: 10.3390/ijms21249766 -
Frontiers in Immunology 2020The Long Pentraxin 3 (PTX3) is a multifunctional glycoprotein released by peripheral blood leukocytes and myeloid dendritic cells in response to primary pro-inflammatory...
The Long Pentraxin 3 (PTX3) is a multifunctional glycoprotein released by peripheral blood leukocytes and myeloid dendritic cells in response to primary pro-inflammatory stimuli, that acts as a non-redundant component of the humoral arm of innate immunity. In addition to the primary role in the acute inflammatory response, PTX3 seems to be involved in other physiological and pathological processes. Indeed, PTX3 seems to play a pivotal role in the deposition and remodeling of bone matrix during the mineralization process, promoting osteoblasts differentiation and activity. Recently, PTX3 was seen to be involved in the ectopic calcifications' formation in breast cancer disease. In this regard, it has been observed that breast cancer tumors characterized by high expression of PTX3 and high amount of Breast Osteoblast Like Cells (BOLCs) showed several Hydroxyapatite (HA) microcalcifications, suggesting a likely role for PTX3 in differentiation and osteoblastic activity in both bone and extra-bone sites. Furthermore, given its involvement in bone metabolism, several studies agree with the definition of PTX3 as a molecule significantly involved in the pathogenesis of age-related bone diseases, such as osteoporosis, both in mice and humans. Recent results suggest that genetic and epigenetic mechanisms acting on gene are also involved in the progression of these diseases. Based on these evidences, the aim of our systemic review was to offer an overview of the variety of biological processes in which PTX3 is involved, focusing on bone mineralization, both in a physiological and pathological context.
Topics: Aging; Animals; C-Reactive Protein; Calcification, Physiologic; Humans; Mice; Nerve Tissue Proteins; Osteoporosis; Serum Amyloid P-Component
PubMed: 33584725
DOI: 10.3389/fimmu.2020.622772 -
Frontiers in Immunology 2018Chemerin [ [retinoic acid receptor responder 2], TIG2 [tazarotene induced gene 2 (TIG2)]] is a multifunctional cytokine initially described in skin cultures upon...
Chemerin [ [retinoic acid receptor responder 2], TIG2 [tazarotene induced gene 2 (TIG2)]] is a multifunctional cytokine initially described in skin cultures upon exposure to the synthetic retinoid tazarotene. Its secreted pro-form, prochemerin, is widely expressed, found systemically, and is readily converted into active chemerin by various proteases. Subsequent studies elucidated major roles of chemerin as both a leukocyte chemoattractant as well as an adipokine. Chemerin's main chemotactic receptor, the G-protein coupled receptor CMKLR1, is expressed on macrophages, dendritic, and NK cells. With respect to its role in immunology, chemerin mediates trafficking of these cells to sites of inflammation along its concentration gradient, and likely helps coordinate early responses, as it has been shown to have antimicrobial and angiogenic properties, as well. Recently, there has been mounting evidence that chemerin is an important factor in various cancers. As with its role in immune responses-where it can act as both a pro- and anti-inflammatory mediator-the potential functions or correlations chemerin has in or with cancer appears to be context dependent. Most studies, however, suggest a downregulation or loss of chemerin/ in malignancies compared to the normal tissue counterparts. Here, we perform a comprehensive review of the literature to date and summarize relevant findings in order to better define the roles of chemerin in the setting of the tumor microenvironment and tumor immune responses, with an ultimate focus on the potential for therapeutic intervention.
Topics: Animals; Chemokines; Dendritic Cells; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Intercellular Signaling Peptides and Proteins; Killer Cells, Natural; Macrophages; Neoplasm Proteins; Neoplasms; Receptors, Chemokine
PubMed: 30555465
DOI: 10.3389/fimmu.2018.02772 -
Cureus Mar 2024Advanced pancreatic cancer is one of the prominent contributors to cancer-related mortality globally. Chemotherapy, especially gemcitabine, is generally used for the... (Review)
Review
Advanced pancreatic cancer is one of the prominent contributors to cancer-related mortality globally. Chemotherapy, especially gemcitabine, is generally used for the treatment of advanced pancreatic cancer. Despite the treatment, the fatality rate for advanced pancreatic cancer is alarmingly high. Thus, the dire need for better treatment alternatives has drawn focus to cancer vaccinations. The Wilms tumor gene (WT1), typically associated with Wilms tumor, is found to be excessively expressed in some cancers, such as pancreatic cancer. This characteristic feature is harvested to develop cancer vaccines against WT1. This review aims to systematically summarize the clinical trials investigating the efficacy and safety of WT1 vaccines in patients with advanced pancreatic cancer. An extensive literature search was conducted on databases Medline, Web of Science, ScienceDirect, and Google Scholar using the keywords "Advanced pancreatic cancer," "Cancer vaccines," "WT1 vaccines," and "Pulsed DC vaccines," and the results were exclusively studied to construct this review. WT1 vaccines work by introducing peptides from the WT1 protein to trigger an immune response involving cytotoxic T lymphocytes via antigen-presenting cells. Upon activation, these lymphocytes induce apoptosis in cancer cells by specifically targeting those with increased WT1 levels. WT1 vaccinations, which are usually given in addition to chemotherapy, have demonstrated clinically positive results and minimal side effects. However, there are several challenges to their widespread use, such as the immunosuppressive nature of tumors and heterogeneity in expression. Despite these limitations, the risk-benefit profile of cancer vaccines is encouraging, especially for the WT1 vaccine in the treatment of advanced pancreatic cancer. Considering the fledgling status of their development, large multicentric, variables-matched, extensive analysis across diverse demographics is considered essential.
PubMed: 38665761
DOI: 10.7759/cureus.56934 -
Critical Care (London, England) Jun 2019Brain injury (BI) induces a state of immunodepression leading to pneumonia. We investigated the invariant natural killer T (iNKT) cell compartment. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Brain injury (BI) induces a state of immunodepression leading to pneumonia. We investigated the invariant natural killer T (iNKT) cell compartment.
METHODS
This is an observational study in two surgical intensive care units (ICUs) of a single institution and a research laboratory. Clinical data and samples from a prospective cohort were extracted. Severe brain-injured patients (n = 33) and sex- and age-matched healthy donors (n = 40) were studied.
RESULTS
We observed the presence of IL-10 in serum, a loss of IFN-γ and IL-13 production by peripheral blood mononuclear cells (PBMCs) following IL-2 stimulation, and downregulation of HLA-DR expression on both monocytes and B cells early after BI. Inversely, CD1d, the HLA class I-like molecule involved in antigen presentation to iNKT cells, was over-expressed on patients' monocytes and B cells. The antigen-presenting activity to iNKT cells of PBMCs was increased in the patients who developed pneumonia, but not in those who remained free of infection. Frequencies of iNKT cells among PBMCs were dramatically decreased in patients regardless of their infection status. Following amplification, an increased frequency of CD4+ iNKT cells producing IL-4 was noticed in the group of patients free of infection compared with those who became infected and with healthy donors. Finally, serum from BI patients inhibited the iNKT cells' specific response as well as the non-specific IL-2 stimulation of PBMCs, and the expression of the beta-2 adrenergic receptor was elevated at the surface of patients T lymphocytes.
CONCLUSIONS
We observed severe alterations of the iNKT cell compartment, including the presence of inhibitory serum factors. We demonstrate for the first time that the decreased capacity to present antigens is not a generalized phenomenon because whereas the expression of HLA-DR molecules is decreased, the capacity for presenting glycolipids through CD1d expression is higher in patients.
Topics: Brain Injuries; Cardiotonic Agents; Cell Compartmentation; Fluid Therapy; Humans; Natural Killer T-Cells
PubMed: 31253189
DOI: 10.1186/s13054-019-2518-2 -
Asian Journal of Surgery Jun 2023
Meta-Analysis
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Cytokines; Immunotherapy; Combined Modality Therapy; Dendritic Cells
PubMed: 36599723
DOI: 10.1016/j.asjsur.2022.12.049 -
International Journal of Molecular... Nov 2021The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and...
What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment.
The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-β, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients' serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells.
Topics: Animals; B7-H1 Antigen; Cell Line, Tumor; Cytokines; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Killer Cells, Natural; Male; Mice; Programmed Cell Death 1 Receptor; Prostatic Neoplasms; T-Lymphocytes, Cytotoxic; Tumor Escape; Tumor Microenvironment; Wnt Signaling Pathway
PubMed: 34830209
DOI: 10.3390/ijms222212330 -
Cytometry. Part B, Clinical Cytometry May 2021
Topics: Aged, 80 and over; CD4 Antigens; CD56 Antigen; Dendritic Cells; Flow Cytometry; Humans; Leukemia, Myelomonocytic, Chronic; Male; Myeloproliferative Disorders; Skin Neoplasms
PubMed: 32830878
DOI: 10.1002/cyto.b.21932 -
PloS One 2018Idiopathic pulmonary fibrosis (IPF) urgently requires effective treatment. Bleomycin-induced lung injury models are characterized by initial inflammation and secondary... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) urgently requires effective treatment. Bleomycin-induced lung injury models are characterized by initial inflammation and secondary fibrosis, consistent with the pathological features of IPF. Human amniotic epithelial cells (hAECs) exhibit good differentiation potential and paracrine activity and are thus ideal for cell-based clinical therapies. The therapeutic effects of hAECs on lung fibrosis are attributed to many factors. We performed a systematic review of preclinical studies investigating the treatment of pulmonary fibrosis with hAECs to provide suggestions for their clinical use.
METHODS
PubMed and EMBASE were searched for original studies describing hAEC therapy in animal bleomycin-induced pulmonary fibrosis models. After quality assessments, the number and species of experimental animals, bleomycin dose, hAEC source and dosage, time and route of administration of transplanted cells in animals, and time animals were euthanized in nine controlled preclinical studies were summarized. Ashcroft scores, lung collagen contents, inflammatory cells and cytokines were quantitatively and/or qualitatively analyzed in this review. Publication bias was also assessed.
RESULTS
Each of the nine preclinical studies have unique characteristics regarding hAEC use. Ashcroft scores and lung collagen contents were decreased following hAEC transplantation in bleomycin-injured mice. Histopathology was also improved in most studies following treatment with hAECs. hAECs modulated macrophages, neutrophils, T cells, dendritic cells and the mRNA or protein levels of cytokines associated with inflammatory reactions (tumor necrosis factor-α, transforming growth factor-β, interferon-γ and interleukin) in lung tissues of bleomycin-injured mice.
CONCLUSIONS
hAECs alleviate and reverse the progression of bleomycin-induced lung fibrosis in mice and may represent a new clinical treatment for IPF. hAECs exert anti-inflammatory and anti-fibrotic effects by modulating macrophage, neutrophil, T cell, dendritic cell and related cytokine levels in mice with bleomycin-induced lung fibrosis. Cell generation and the route, source and timing of hAEC transplantation all determine the therapeutic effectiveness of hAECs.
Topics: Amnion; Animals; Bleomycin; Collagen; Cytokines; Dendritic Cells; Disease Models, Animal; Epithelial Cells; Fibrosis; Heterografts; Humans; Inflammation; Lung; Macrophages; Mice; Neutrophils; Pulmonary Fibrosis; T-Lymphocyte Subsets
PubMed: 29772024
DOI: 10.1371/journal.pone.0197658