TIGIT Dotaz Zobrazit nápovědu
Accumulating evidence indicates that immune checkpoint inhibitors (ICIs) can restore CD8+ cytotoxic T lymphocyte (CTL) functions in preclinical models of acute myeloid leukemia (AML). However, ICIs targeting programmed cell death 1 (PDCD1, best known as PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4) have limited clinical efficacy in patients with AML. Natural killer (NK) cells are central players in AML-targeting immune responses. However, little is known on the relationship between co-inhibitory receptors expressed by NK cells and the ability of the latter to control AML. Here, we show that hepatitis A virus cellular receptor 2 (HAVCR2, best known as TIM-3) is highly expressed by NK cells from AML patients, correlating with improved functional licensing and superior effector functions. Altogether, our data indicate that NK cell frequency as well as TIM-3 expression levels constitute prognostically relevant biomarkers of active immunity against AML.
- Klíčová slova
- Co-inhibitory receptor, innate lymphoid cells, lag-3, tigit, vista,
- MeSH
- akutní myeloidní leukemie * farmakoterapie MeSH
- buněčný receptor 2 viru hepatitidy A * MeSH
- buňky NK * MeSH
- CD8-pozitivní T-lymfocyty MeSH
- cytotoxické T-lymfocyty MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- buněčný receptor 2 viru hepatitidy A * MeSH
- HAVCR2 protein, human MeSH Prohlížeč
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
- Názvy látek
- biologické markery MeSH
T-cell lymphomas (TCLs) are a rare and heterogeneous subgroup of non-Hodgkin lymphomas (NHLs), forming only 10 % of all NHL cases in Western countries. Resulting from their low incidence and heterogeneity, the current treatment outcome is generally unfavorable, with limited availability of novel therapeutic approaches. Therefore, the recent success of immune checkpoint inhibitors (ICIs) in cancer treatment motivated their clinical investigation in TCLs as well. Multiple studies showed promising results; however, cases of TCL hyperprogression following ICI treatment and secondary T-cell-derived malignancies associated with ICI treatment of other cancer types were also reported. In our review, we first briefly summarize classification of T-cell-derived malignancies, general anti-tumor immune response, immune evasion, and immune checkpoint signaling. Next, we provide an overview of immune checkpoint molecule deregulation in TCLs, summarize available studies of ICIs in TCLs, and review the above-mentioned safety concerns associa-ted with ICI treatment and T-cell-derived malignancies. Despite initial promising results, further studies are necessary to define the most suitable clinical applications and ICI therapeutic combinations with other novel treatment approaches within TCL treatment. ICIs, and their combinations, might hopefully bring the long awaited improvement for the treatment of T-cell-derived malignancies.
- Klíčová slova
- ALCL, CTLA-4, ENKTL, LAG-3, MF, OX40/OX40L, PD-1, PD-L1, PTCL, SS, Sézary syndrome, T-cell lymphoma, T-cell-derived malignancies, TIGIT, TIM-3, anaplastic large cell lymphoma, anti-CTLA-4, anti-PD-1, anti-PD-L1, atezolizumab, avelumab, durvalumab, extranodal NK/T-cell lymphoma, geptanolimab, immune checkpoint inhibitors, immune checkpoints, ipilimumab, mycosis fungoides, nivolumab, pembrolizumab, peripheral T-cell lymphoma, sintilimab, toripalimab,
- MeSH
- inhibitory kontrolních bodů * terapeutické užití MeSH
- lidé MeSH
- lymfom T-buněčný * farmakoterapie imunologie MeSH
- proteiny kontrolních bodů imunitní reakce metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- inhibitory kontrolních bodů * MeSH
- proteiny kontrolních bodů imunitní reakce 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.
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.
- Klíčová slova
- AML, NK cells, T cells, bone marrow, checkpoint inhibitors, high‐dimensional flow cytometry, immune checkpoint, immunotherapy, inhibitory ligands, leukemic stem cells,
- 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
- Názvy látek
- proteiny kontrolních bodů imunitní reakce MeSH
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.
- Klíčová slova
- Activation, CVID, Differentiation, Exhaustion, Immunodeficiency, T cells,
- MeSH
- antigeny CD279 genetika MeSH
- antigeny CD28 MeSH
- běžná variabilní imunodeficience * MeSH
- CD8-pozitivní T-lymfocyty MeSH
- HLA-DR antigeny MeSH
- interleukin-10 MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antigeny CD279 MeSH
- antigeny CD28 MeSH
- HLA-DR antigeny MeSH
- interleukin-10 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.
- Klíčová slova
- B-cell lymphoma and leukemia, CAR-T cells, Kymriah, immunotherapy, tisagenlecleucel,
- MeSH
- B-buněčný lymfom * MeSH
- CD8-pozitivní T-lymfocyty metabolismus MeSH
- difúzní velkobuněčný B-lymfom * patologie MeSH
- imunoterapie adoptivní metody MeSH
- lidé MeSH
- průtoková cytometrie MeSH
- receptory antigenů T-buněk metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- receptory antigenů T-buněk MeSH
- tisagenlecleucel MeSH Prohlížeč
