• Publikační typ
• zprávy MeSH

BACKGROUND: Immune checkpoint inhibitors (ICIs), including those targeting PD-1, are currently used in a wide range of tumors, but only 20-40% of patients achieve clinical benefit. The objective of our study was to find predictive peripheral blood-based biomarkers for ICI treatment. METHODS: In 41 patients with advanced malignant melanoma (MM) and NSCLC treated with PD-1 inhibitors, we analyzed peripheral blood-based immune subsets by flow cytometry before treatment initialization and the second therapy dose. Specifically, we assessed basic blood differential count, overall T cells and their subgroups, B cells, and myeloid-derived suppressor cells (MDSC). In detail, CD4 + and CD8 + T cells were assessed according to their subtypes, such as central memory T cells (TCM), effector memory T cells (TEM), and naïve T cells (TN). Furthermore, we also evaluated the predictive value of CD28 and ICOS/CD278 co-expression on T cells. RESULTS: Patients who achieved disease control on ICIs had a significantly lower baseline proportion of CD4 + TEM (p = 0.013) and tended to have a higher baseline proportion of CD4 + TCM (p = 0.059). ICI therapy-induced increase in Treg count (p = 0.012) and the proportion of CD4 + TN (p = 0.008) and CD28 + ICOS- T cells (p = 0.012) was associated with disease control. Patients with a high baseline proportion of CD4 + TCM and a low baseline proportion of CD4 + TEM showed significantly longer PFS (p = 0.011, HR 2.6 and p ˂ 0.001, HR 0.23, respectively) and longer OS (p = 0.002, HR 3.75 and p ˂ 0.001, HR 0.15, respectively). Before the second dose, the high proportion of CD28 + ICOS- T cells after ICI therapy initiation was significantly associated with prolonged PFS (p = 0.017, HR 2.51) and OS (p = 0.030, HR 2.69). Also, a high Treg count after 2 weeks of ICI treatment was associated with significantly prolonged PFS (p = 0.016, HR 2.33). CONCLUSION: In summary, our findings suggest that CD4 + TEM and TCM baselines and an early increase in the Treg count induced by PD-1 inhibitors and the proportion of CD28 + ICOS- T cells may be useful in predicting the response in NSCLC and MM patients.

• MeSH
• antigeny CD278 metabolismus   MeSH
• antigeny CD279 antagonisté a inhibitory   MeSH
• antigeny CD28 MeSH
• CD8-pozitivní T-lymfocyty imunologie   účinky léků   metabolismus   MeSH
• dospělí MeSH
• inhibitory kontrolních bodů * terapeutické užití   farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• melanom * farmakoterapie   imunologie   krev   patologie   MeSH
• nádory plic * farmakoterapie   imunologie   krev   patologie   MeSH
• nemalobuněčný karcinom plic * farmakoterapie   imunologie   krev   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Onkologická léčba je dnes považována za nezávislý kardiovaskulární rizikový faktor. Základní léčbu chronické myeloidní leukemie (CML) představují v současnosti inhibitory BCR:ABL1 tyrozinkinázy (TKI). Zatímco inhibitor první generace (imatinib) se jevil z kardiovaskulárního hlediska jako relativně bezpečný, bylo zavedení TKI 2. a 3. generace spojeno s nárůstem kardiovaskulárních příhod i zhoršením jejich rizikových faktorů, především hypertenze, hyperglykemie, dyslipidemie a renální insuficience. Další zaznamenané vedlejší účinky zahrnují plicní hypertenzi, perikardiální i pleurální exsudáty, arytmie a v menší míře žilní trombózy. Před zahájením vlastní hematoonkologické léčby je proto vždy třeba provést stanovení individuálního kardiovaskulárního rizika podle SCORE2, SCORE2-OP či SCORE2-DM, určit kardiovaskulární toxicitu daného preparátu podle recentních kardio-onkologických doporučení ECS (ICOS) a provádět pravidelné kontroly vybraných parametrů v průběhu léčby (TK, lipidogram, HbA1c, vyšetření moče a eGFR, ABR, TTE, EKG) s ohledem na příslušný TKI.

The oncology therapy represents an independent cardiovascular risk factor. For chronic myeloid leukemia (CML), the BCR:ABL1 tyrosine kinase inhibitors (TKI) have become the frontline therapy. While the first generation inhibitor (imatinib) revealed a relatively safe cardiovascular profile, the introduction of the second and third generation TKIs was associated with an in -crease of cardiovascular events as well as worsening of their risk factors, esp. hypertension, hyperglycemia, dyslipidemia and renal failure. Other observed side effects include pulmonary hypertension, pericardial and pleural effusions, arrhythmias and to lesser extent venous thrombosis. Before initiating the hemato-oncology therapy, it is necessary to assess the individual cardiovascular risk using SCORE2, SCORE2-OP or SCORE2-DM charts/calculators as well as to estimate the drug cardiovas -cular toxicity according to the recent ECS cardio-oncology guidelines (ICOS) and to perform regular follow-up of selected parameters during the TKI therapy (BP, blood lipids, HbA1c, urine analysis, eGFR, ABR, ecg) with respect to the specific TKI.

• MeSH
• chronická myeloidní leukemie farmakoterapie   MeSH
• inhibitory tyrosinkinasy * škodlivé účinky   MeSH
• lidé MeSH
• nežádoucí účinky léčiv MeSH
• rizikové faktory kardiovaskulárních chorob * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Triacylglycerols (TGs) stored in the fat bodies of bumblebee males have a species-specific composition. The striking structural similarities between TG fatty acids (FAs) and components of the male marking pheromone in certain species led to the hypothesis that FAs may serve as precursors in pheromone biosynthesis. Here, we analysed TGs from B. ruderatus, B. bohemicus, and B. campestris. Nonadec-9-ene and icos-15-en-1-ol are the main components of B. ruderatus labial gland secretion, forming up to 92% of the gland extract. The corresponding icos-11-enic and icos-15-enic acids were found in TGs at levels higher than usual for bumblebee species. We found similar relationships in B. campestris and B. bohemicus. These results suggest that FAs might be precursors of aliphatic compounds in the male pheromones. Furthermore, we report for the first time the pheromone structure of B. ruderatus males.

• MeSH
• druhová specificita MeSH
• feromony chemie   sekrece   MeSH
• lipidy chemie   MeSH
• mastné kyseliny chemie   MeSH
• sexuální lákadla chemie   MeSH
• včely chemie   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

γδ T lymfocyty představují menšinovou populaci T lymfocytů, která se v základu liší konstrukcí TCR receptoru. Unikátní vlastnosti γδ TCR dávají pak těmto buňkám jedinečné efektorové funkce a specifickou roli (nejen) v protinádorové imunitní odpovědi. V tomto článku popisujeme základní charakteristiku těchto buněk ve vztahu k onkologickým onemocněním. V experimentální části je pak provedena exploratorní analýza zastoupení γδ T lymfocytů v běžné populaci a srovnání těchto hodnot s hodnotami pacientů s melanomem a karcinomem prsu. Medián procentuálního zastoupení γδ ze všech lymfocytů byl 2,9 % (interkvartilové rozpětí – IQR 1,7– 4 %). Medián absolutních počtů γδ buněk v litru krve byl 5,05 × 107 (IQR 2,9– 7,84 × 107). Medián procentuálního zastoupení γδ buněk mezi T lymfocyty byl 3,9 % (IQR 2,3– 5,6 %). V referenční populaci nebyla prokázána závislost kvantitativních parametrů γδ buněk na pohlaví či věku. Dále proběhla detailní imunofenotypizace popisující zastoupení paměťových subpopulací (pomocí značení CD45RO a CD27) a výskyt povrchových markerů HLA‑Dr, CD69, CD25, CD28, CCR7, CTLA‑ 4, ICOS, PD‑ 1L a PD‑ 1 mezi γδ T lymfocyty u kontrol a pacientek s karcinomem prsu. Z této analýzy je patrné, že γδ buňky netvoří uniformní populaci, ale mohou se ve svých povrchových markerech lišit, stejně jako se pak liší v efektorových funkcích.

γδ T cells present a minor population of the T cell family which basically differs in construction of their T cell receptor (TCR). Thanks to the features of γδ TCR, these cells can acquire unique effector functions and play a specific role (not only) in anti‑tumor immune response. In this article, we describe the basic characteristics of this cell population and their connection to cancer. In the experimental part we performed exploratory analysis of circulating γδ T cells in reference population and comparison with melanoma and breast carcinoma patients. The median percentage of γδ T cells from all lymphocytes was 2.9% (interquartile range – IQR 1.7– 4%). The median absolute numbers of γδ cells per liter of blood was 5.05 × 107 (IQR 2.9– 7.84 × 107). The median percentage of γδ cells between all CD3 T cells was 3.9% (IQR 2.3– 5.6%). No correlation between γδ T cells levels and gender or age was observed in reference population. Detailed immunophenotyping was also conducted describing representation of memory subsets (using CD45RO and CD27 markers) and presence of surface markers HLA‑Dr, CD69, CD25, CD28, CCR7, CTLA‑ 4, ICOS, PD‑ 1L and PD‑ 1 between γδ T cells of the controls and breast carcinoma patients. From this analysis, it is evident that γδ T cells do not represent a uniform population but they differ in surface markers as well as in their effector functions.

• Klíčová slova
• γδ T-lymfocyty,
• MeSH
• dospělí MeSH
• imunitní systém MeSH
• imunofenotypizace MeSH
• imunoterapie adoptivní metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• melanom krev   metabolismus   MeSH
• nádory kůže krev   metabolismus   MeSH
• nádory prsu krev   metabolismus   MeSH
• nádory * farmakoterapie   imunologie   MeSH
• průtoková cytometrie statistika a číselné údaje   MeSH
• receptory antigenů T-buněk gama-delta * fyziologie   imunologie   terapeutické užití   MeSH
• rozložení podle pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• statistika jako téma MeSH
• studie případů a kontrol MeSH
• T-lymfocyty * imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• práce podpořená grantem MeSH

Plasmacytoid dendritic cells (pDCs) are a minority subset of dendritic cells that despite their tiny quantity play an important role in the immune system, especially in antiviral immunity. They are known mostly as the major producers of type I IFN, which they secrete upon stimulation of endosomal Toll-like receptors 7 and 9 with viral RNA and DNA. However, the functionality of pDCs is more complex, as they were shown to be also involved in autoimmunity, inflammation, and cancer. In the context of the tumor microenvironment, pDCs mostly show substantial functional defects and thus contribute to establishing immunosuppressive micromilieu. Indeed, tumor-infiltrating pDCs were shown to be predominantly pro-tumorigenic, with reduced ability to produce IFNα and capacity to prime regulatory T cells via the ICOS/ICOS-L pathway. Here we describe in detail a method to assess the functional capacity of pDCs upon exposure to tumor-derived cell culture supernatants. The same technique can be implemented with minimal variations to test any soluble factor's impact on pDC phenotype and function.

• MeSH
• dendritické buňky * imunologie   metabolismus   MeSH
• lidé MeSH
• nádorové mikroprostředí imunologie   MeSH
• nádory * imunologie   patologie   metabolismus   MeSH
• průtoková cytometrie metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Head and neck squamous cell carcinomas (HNSCCs) belong to a group of diverse tumors, which can be induced by infection with human papillomavirus (HPV) or tobacco and alcohol consumption. The viral etiology of HNSCC relates to better clinical outcomes reflecting a different immune system response. Here, we retrospectively analyzed 97 tissue samples from oral and oropharyngeal carcinomas associated and non-associated with HPV infection using multispectral fluorescent immunohistochemistry. To evaluate the immune cell infiltration in tumor and stroma compartments, we designed four panels of four to five antibodies. We detected more T lymphocytes in the stroma, compared to the tumor parenchyma. In HPV positive (HPV+) in comparison to HPV negative (HPV-) tumors, higher counts of CD3+CD4+, CD3+CD8+, PD1+CD4+, PD1+CD8+ T cells, and ICOS- Treg cells were detected while more ICOS+ Treg cells and CTLA4+CD4+ T cells were observed in HPV- than in HPV+ tumors. The results of the univariate and multivariate analyses confirmed the predominant impact of HPV status on prognosis. More importantly, the number of CD8+PD-1+ T cells was identified as an independent factor, influencing the overall and/or disease-specific survival of patients with oral cavity or oropharyngeal carcinomas.

• Publikační typ
• časopisecké články MeSH

Plasmacytoid dendritic cells (pDCs) are the most potent type I interferon-producing cells and play an important role in antiviral immunity. Tumor-infiltrating pDCs were shown to be predominantly pro-tumorigenic, with reduced ability to produce interferon alpha (IFNα) and confirmed capacity to prime regulatory T cells (Tregs) by the ICOS/ICOS-L pathway. Because a significant number of HNSCCs are induced by human papillomaviruses and show markedly different immune profiles than non-virally induced tumors, we compared the phenotype and functional capacity of HNSCC-infiltrating pDCs to the HPV status of the tumor. We observed a reduced capacity of pDCs to produce IFNα upon toll-like receptor activation in HPV-negative samples and a rather uncompromised functionality in HPV-associated tumors. Additionally, supernatants from non-virally induced but not HPV-associated tumor cell suspensions significantly inhibited IFNα production by peripheral blood-derived pDCs. We identified IL-10 and TNFα as the soluble pDC-suppressive factors with the highest variability between HPV-negative and HPV-positive tumor-derived supernatants. Additionally, we observed a positive correlation of tumor-infiltrating pDCs with Tregs in HPV-negative samples but not in virally induced tumors. Overall, our study indicates that the immunosuppressive cytokine milieu rich in IL-10 and TNFα in HPV-negative but not in HPV-positive HNSCC significantly affects the functional capacity of tumor-infiltrating pDCs, and such dysfunctional pDCs may further support the immunosuppressive tumor microenvironment by promoting the expansion of Tregs in the tumor tissue.

• MeSH
• biologické markery MeSH
• cytokiny metabolismus   MeSH
• dendritické buňky imunologie   metabolismus   patologie   MeSH
• dlaždicobuněčné karcinomy hlavy a krku etiologie   metabolismus   patologie   MeSH
• exprese genu MeSH
• infekce papilomavirem komplikace   virologie   MeSH
• interferon alfa imunologie   metabolismus   MeSH
• lidé MeSH
• náchylnost k nemoci MeSH
• nádorové mikroprostředí * imunologie   MeSH
• regulační T-lymfocyty imunologie   metabolismus   MeSH
• studie případů a kontrol MeSH
• T-lymfocyty - podskupiny imunologie   metabolismus   MeSH
• virová transformace buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The heterogeneity of common variable immunodeficiency (CVID) calls for a classification addressing pathogenic mechanisms as well as clinical relevance. This European multicenter trial was initiated to develop a consensus of 2 existing classification schemes based on flowcytometric B-cell phenotyping and the clinical course. The clinical evaluation of 303 patients with the established diagnosis of CVID demonstrated a significant coincidence of granulomatous disease, autoimmune cytopenia, and splenomegaly. Phenotyping of B-cell subpopulations confirmed a severe reduction of switched memory B cells in most of the patients that was associated with a higher risk for splenomegaly and granulomatous disease. An expansion of CD21(low) B cells marked patients with splenomegaly. Lymphadenopathy was significantly linked with transitional B-cell expansion. Based on these findings and pathogenic consideration of B-cell differentiation, we suggest an improved classification for CVID (EUROclass), separating patients with nearly absent B cells (less than 1%), severely reduced switched memory B cells (less than 2%), and expansion of transitional (more than 9%) or CD21(low) B cells (more than 10%). Whereas the first group contains all patients with severe defects of early B-cell differentiation, severely reduced switched memory B cells indicate a defective germinal center development as found in inducible constimulator (ICOS) or CD40L deficiency. The underlying defects of expanded transitional or CD21(low) B cells remain to be elucidated. This trial is re-gistered at http://www.uniklinik-freiburg.de/zks/live/uklregister/Oeffentlich.html as UKF000308.

• MeSH
• B-lymfocyty imunologie   patologie   MeSH
• běžná variabilní imunodeficience * epidemiologie   imunologie   klasifikace   patologie   MeSH
• dospělí MeSH
• homeostáza imunologie   MeSH
• imunofenotypizace * MeSH
• imunoglobuliny krev   MeSH
• kohortové studie MeSH
• konsensus MeSH
• lidé středního věku MeSH
• lidé MeSH
• průtoková cytometrie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH

DiGeorge syndrome is an immunodeficiency characterized by thymic dysplasia resulting in T cell lymphopenia. Most patients suffer from increased susceptibility to infections and heightened prevalence of autoimmune disorders, such as autoimmune thrombocytopenia. B cells in DiGeorge syndrome show impaired maturation, with low switched-memory B cells and a wide spectrum of antibody deficiencies or dysgammaglobulinemia, presumably due to impaired germinal center responses. We set out to evaluate circulating follicular helper T cells (cTFHs) in DiGeorge syndrome, as markers of T-B interaction in the germinal centers in a cohort of 17 patients with partial DiGeorge and 21 healthy controls of similar age. cTFHs were characterized as CXCR5+CD45RA- CD4+ T cells using flow cytometry. We verify previous findings that the population of memory CD4+ T cells is relatively increased in diGeorge patients, corresponding to low naïve T cells and impaired T cell production in the thymus. The population of CXCR5+ memory CD4+ T cells (cTFHs) was significantly expanded in patients with DiGeorge syndrome, but only healthy controls and not DiGeorge syndrome patients showed gradual increase of CXCR5 expression on cTFHs with age. We did not observe correlation between cTFHs and serum IgG levels or population of switched memory B cells. There was no difference in cTFH numbers between DiGeorge patients with/without thrombocytopenia and with/without allergy. Interestingly, we show strong decline of PD1 expression on cTFHs in the first 5 years of life in DiGeorge patients and healthy controls, and gradual increase of PD1 and ICOS expression on CD4- T cells in healthy controls later in life. Thus, here, we show that patients with DiGeorge syndrome have elevated numbers of cTFHs, which, however, do not correlate with autoimmunity, allergy, or production of immunoglobulins. This relative expansion of cTFH cells may be a result of impaired T cell development in patients with thymic dysplasia.

• Publikační typ
• časopisecké články MeSH