tigit Dotaz Zobrazit nápovědu
- Klíčová slova
- tiragolumab, atezolizumab,
- MeSH
- antitumorózní látky aplikace a dávkování MeSH
- imunoterapie * metody MeSH
- kombinovaná farmakoterapie MeSH
- lidé MeSH
- monoklonální protilátky aplikace a dávkování farmakologie MeSH
- nemalobuněčný karcinom plic farmakoterapie MeSH
- randomizované kontrolované studie jako téma MeSH
- receptory imunologické fyziologie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
Za poslední dekádu se imunoterapie etablovala do léčebného algoritmu napříč mnohých solidních tumorů. A i přes to, že etablování checkpoint inhibitorů vůči PD-1 a CTLA-4 receptorům a PD-1 ligandu přináší léčebný benefit, existuje stále velká skupina pacientů, u kterých tato terapie není účinná. V současné době probíhá další výzkum, který se snaží najít další možné způsoby, jak dosáhnout dalšího zlepšení. V následujícím článku jsou prezentovány méně známé checkpoint inhibitory, které mají v blízké budoucnosti terapeutický potenciál.
Over the last decade, immunotherapy has been established as part of various treatment algorithms across solid tumors. And although the use of checkpoint inhibitors like anti-PD-1 and anti-CTLA-4 receptors and anti-PD-1 ligand provides a therapeutic benefit, there is still a large group of patients in whom this therapy is not effective. Further research is currently underway to find other possible ways to make improvements. In the following article, we present less known checkpoint inhibitors which have therapeutic potential in the near future.
- Klíčová slova
- LAG-3, TIM-3, TIGIT,
- MeSH
- imunoterapie * metody MeSH
- inhibitory kontrolních bodů * farmakologie terapeutické užití MeSH
- lidé MeSH
- nádory * farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
T cell memory relies on the generation of antigen-specific progenitors with stem-like properties. However, the identity of these progenitors has remained unclear, precluding a full understanding of the differentiation trajectories that underpin the heterogeneity of antigen-experienced T cells. We used a systematic approach guided by single-cell RNA-sequencing data to map the organizational structure of the human CD8+ memory T cell pool under physiological conditions. We identified two previously unrecognized subsets of clonally, epigenetically, functionally, phenotypically and transcriptionally distinct stem-like CD8+ memory T cells. Progenitors lacking the inhibitory receptors programmed death-1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were committed to a functional lineage, whereas progenitors expressing PD-1 and TIGIT were committed to a dysfunctional, exhausted-like lineage. Collectively, these data reveal the existence of parallel differentiation programs in the human CD8+ memory T cell pool, with potentially broad implications for the development of immunotherapies and vaccines.
- MeSH
- biologické markery MeSH
- buněčná diferenciace imunologie MeSH
- CD8-pozitivní T-lymfocyty imunologie metabolismus MeSH
- homeostáza telomer MeSH
- imunofenotypizace MeSH
- imunologická paměť * MeSH
- lidé MeSH
- lymfoidní progenitorové buňky cytologie imunologie metabolismus MeSH
- myši MeSH
- stanovení celkové genové exprese MeSH
- T-lymfocyty - podskupiny imunologie metabolismus MeSH
- výpočetní biologie metody MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
This 29-color panel was developed and optimized for the monitoring of NK cell and T cell reconstitution in peripheral blood of patients after HSCT. We considered major post-HSCT complications during the design, such as relapses, viral infections, and GvHD and identification of lymphocyte populations relevant to their resolution. The panel includes markers for all major NK cell and T cell subsets and analysis of their development and qualitative properties. In the NK cell compartment, we focus mainly on CD57 + NKG2C+ cells and the expression of activating (NKG2D, DNAM-1) and inhibitory receptors (NKG2A, TIGIT). Another priority is the characterization of T cell reconstitution; therefore, we included detection of CD4+ RTEs based on CD45RA, CD62L, CD95, and CD31 as a marker of thymus function. Besides that, we also analyze the emergence and properties of major T cell populations with a particular interest in CD8, Th1, ThCTL, and Treg subsets. Overall, the panel allows for comprehensive analysis of the reconstituting immune system and identification of potential markers of immune cell dysfunction.
We aimed to explore the development and cell communication of osteoblasts and osteoclasts with aneuploidy variation in giant cell tumour of bone (GCTB). We predicted the diploid and aneuploid cells in tissue samples using the CopyKAT package. The Monocle2 package was used to analyse differentiation trajectories of aneuploid cells. We used the CellChat package to observe the signalling pathways and ligand-receptor pairs for the two interaction types, "Cell-Cell Contact" and "Secreted Signalling", respectively. A total of 9,117 cells were obtained including eight cell types. Most aneuploid cells were osteoblasts. As the cell differentiation trajectory matured, we found that aneuploid osteoblasts first increased the inflammatory response activity and then enhanced the ability to activate T cells, whereas osteoclasts gradually enhanced the cellular energy metabolism, cell adhesion, cell proliferation and immune response; the activated biological functions were gradually weakened. The analysis by CellChat indicated that CTLA4 or TIGIT might act as important immune checkpoint genes to attenuate the inhibitory effect of aneuploid osteoclasts on NK/T cells, thereby enhancing the activity of NK/T cells. Our study found that both osteoblasts and osteoclasts might be involved in the development of GCTB, which may provide a new direction for the treatment of GCTB.
- MeSH
- analýza jednotlivých buněk * MeSH
- aneuploidie * MeSH
- buněčná diferenciace genetika MeSH
- lidé MeSH
- mezibuněčná komunikace * genetika MeSH
- nádory kostí genetika patologie metabolismus MeSH
- obrovskobuněčný nádor kosti * genetika patologie MeSH
- osteoblasty * metabolismus MeSH
- osteoklasty * metabolismus patologie MeSH
- sekvenční analýza RNA metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency, with heterogeneous clinical presentation. Our goal was to analyze CD8 T cell homeostasis in patients with infection only CVID, compared to those additionally affected by dysregulatory and autoimmune phenomena. METHODS: We used flow and mass cytometry evaluation of peripheral blood of 40 patients with CVID and 17 healthy donors. RESULTS: CD8 T cells are skewed in patients with CVID, with loss of naïve and increase of effector memory stages, expansion of cell clusters with high functional exhaustion scores, and a highly activated population of cells with immunoregulatory features, producing IL-10. These findings correlate to clinically widely used B cell-based EURO classification. Features of exhaustion, including loss of CD127 and CD28, and expression of TIGIT and PD-1 in CD8 T cells are strongly associated with interstitial lung disease and autoimmune cytopenias, whereas CD8 T cell activation with elevated HLA-DR and CD38 expression predict non-infectious diarrhea. CONCLUSION: We demonstrate features of advanced differentiation, exhaustion, activation, and immunoregulatory capabilities within CD8 T cells of CVID patients. Assessment of CD8 T cell phenotype may allow risk assessment of CVID patients and provide new insights into CVID pathogenesis, including a better understanding of mechanisms underlying T cell exhaustion and regulation.
Acute myeloid leukemia (AML) is the most common form of acute leukemia diagnosed in adults. Despite advances in medical care, the treatment of AML still faces many challenges, such as treatment-related toxicities, that limit the use of high-intensity chemotherapy, especially in elderly patients. Currently, various immunotherapeutic approaches, that is, CAR-T cells, BiTEs, and immune checkpoint inhibitors, are being tested in clinical trials to prolong remission and improve the overall survival of AML patients. However, early reports show only limited benefits of these interventions and only in a subset of patients, showing the need for better patient stratification based on immunological markers. We have therefore developed and optimized a 30-color panel for evaluation of effector immune cell (NK cells, γδ T cells, NKT-like T cells, and classical T cells) infiltration into the bone marrow and analysis of their phenotype with regard to their differentiation, expression of inhibitory (PD-1, TIGIT, Tim3, NKG2A) and activating receptors (DNAM-1, NKG2D). We also evaluate the immune evasive phenotype of CD33+ myeloid cells, CD34+CD38-, and CD34+CD38+ hematopoietic stem and progenitor cells by analyzing the expression of inhibitory ligands such as PD-L1, CD112, CD155, and CD200. Our panel can be a valuable tool for patient stratification in clinical trials and can also be used to broaden our understanding of check-point inhibitory networks in AML.
- MeSH
- akutní myeloidní leukemie * imunologie patologie MeSH
- buňky NK imunologie MeSH
- kostní dřeň * patologie imunologie MeSH
- lidé MeSH
- průtoková cytometrie metody MeSH
- T-lymfocyty imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
COVID-19 (Coronavirus Disease) is an infectious disease caused by the coronavirus SARS-CoV-2 (Severe acute respiratory syndrome Coronavirus 2), which belongs to the genus Betacoronavirus. It was first identified in patients with severe respiratory disease in December 2019 in Wuhan, China. It mainly affects the respiratory system, and in severe cases causes serious lung infection or pneumonia, which can lead to the death of the patient. Clinical studies show that SARS-CoV-2 infection in critical cases causes acute tissue damage due to a pathological immune response. The immune response to a new coronavirus is complex and involves many processes of specific and non-specific immunity. Analysis of available studies has shown various changes, especially in the area of specific cellular immunity, including lymphopenia, decreased T cells (CD3+, CD4+ and CD8+), changes in the T cell compartment associated with symptom progression, deterioration of the condition and development of lung damage. We provide a detailed review of the analyses of immune checkpoint molecules PD-1, TIM-3, LAG-3 CTLA-4, TIGIT, BTLA, CD223, IDO-1 and VISTA on exhausted T cells in patients with asymptomatic to symptomatic stages of COVID-19 infection. Furthermore, this review may help to better understand the pathological T cell immune response and improve the design of therapeutic strategies for patients with SARS-CoV-2 infection.
- MeSH
- COVID-19 imunologie metabolismus virologie MeSH
- fenotyp MeSH
- interakce hostitele a patogenu MeSH
- lidé MeSH
- proteiny kontrolních bodů imunitní reakce metabolismus MeSH
- SARS-CoV-2 imunologie patogenita MeSH
- signální transdukce MeSH
- T-lymfocyty imunologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Tisagenlecleucel (tisa-cel) is a CD19-specific CAR-T cell product approved for the treatment of relapsed/refractory (r/r) DLBCL or B-ALL. We have followed a group of patients diagnosed with childhood B-ALL (n = 5), adult B-ALL (n = 2), and DLBCL (n = 25) who were treated with tisa-cel under non-clinical trial conditions. The goal was to determine how the intensive pretreatment of patients affects the produced CAR-T cells, their in vivo expansion, and the outcome of the therapy. Multiparametric flow cytometry was used to analyze the material used for manufacturing CAR-T cells (apheresis), the CAR-T cell product itself, and blood samples obtained at three timepoints after administration. We present the analysis of memory phenotype of CD4/CD8 CAR-T lymphocytes (CD45RA, CD62L, CD27, CD28) and the expression of inhibitory receptors (PD-1, TIGIT). In addition, we show its relation to the patients' clinical characteristics, such as tumor burden and sensitivity to prior therapies. Patients who responded to therapy had a higher percentage of CD8+CD45RA+CD27+ T cells in the apheresis, although not in the produced CAR-Ts. Patients with primary refractory aggressive B-cell lymphomas had the poorest outcomes which was characterized by undetectable CAR-T cell expansion in vivo. No clear correlation of the outcome with the immunophenotypes of CAR-Ts was observed. Our results suggest that an important parameter predicting therapy efficacy is CAR-Ts' level of expansion in vivo but not the immunophenotype. After CAR-T cells' administration, measurements at several timepoints accurately detect their proliferation intensity in vivo. The outcome of CAR-T cell therapy largely depends on biological characteristics of the tumors rather than on the immunophenotype of produced CAR-Ts.
