Intratumoral tertiary lymphoid structures (TLSs) have been associated with improved outcome in various cohorts of patients with cancer, reflecting their contribution to the development of tumor-targeting immunity. Here, we demonstrate that high-grade serous ovarian carcinoma (HGSOC) contains distinct immune aggregates with varying degrees of organization and maturation. Specifically, mature TLSs (mTLS) as forming only in 16% of HGSOCs with relatively elevated tumor mutational burden (TMB) are associated with an increased intratumoral density of CD8+ effector T (TEFF) cells and TIM3+PD1+, hence poorly immune checkpoint inhibitor (ICI)-sensitive, CD8+ T cells. Conversely, CD8+ T cells from immunologically hot tumors like non-small cell lung carcinoma (NSCLC) are enriched in ICI-responsive TCF1+ PD1+ T cells. Spatial B-cell profiling identifies patterns of in situ maturation and differentiation associated with mTLSs. Moreover, B-cell depletion promotes signs of a dysfunctional CD8+ T cell compartment among tumor-infiltrating lymphocytes from freshly isolated HGSOC and NSCLC biopsies. Taken together, our data demonstrate that - at odds with NSCLC - HGSOC is associated with a low density of follicular helper T cells and thus develops a limited number of mTLS that might be insufficient to preserve a ICI-sensitive TCF1+PD1+ CD8+ T cell phenotype. These findings point to key quantitative and qualitative differences between mTLSs in ICI-responsive vs ICI-irresponsive neoplasms that may guide the development of alternative immunotherapies for patients with HGSOC.
- MeSH
- CD8-pozitivní T-lymfocyty MeSH
- ektopické lymfoidní struktury * MeSH
- fenotyp MeSH
- lidé MeSH
- nádorové mikroprostředí MeSH
- nádory plic * MeSH
- nádory vaječníků * patologie MeSH
- nemalobuněčný karcinom plic * MeSH
- tumor infiltrující lymfocyty MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
While type I interferon (IFN) is best known for its key role against viral infection, accumulating preclinical and clinical data indicate that robust type I IFN production in the tumor microenvironment promotes cancer immunosurveillance and contributes to the efficacy of various antineoplastic agents, notably immunogenic cell death inducers. Here, we report that malignant blasts from patients with acute myeloid leukemia (AML) release type I IFN via a Toll-like receptor 3 (TLR3)-dependent mechanism that is not driven by treatment. While in these patients the ability of type I IFN to stimulate anticancer immune responses was abolished by immunosuppressive mechanisms elicited by malignant blasts, type I IFN turned out to exert direct cytostatic, cytotoxic and chemosensitizing activity in primary AML blasts, leukemic stem cells from AML patients and AML xenograft models. Finally, a genetic signature of type I IFN signaling was found to have independent prognostic value on relapse-free survival and overall survival in a cohort of 132 AML patients. These findings delineate a clinically relevant, therapeutically actionable and prognostically informative mechanism through which type I IFN mediates beneficial effects in patients with AML.
- MeSH
- akutní myeloidní leukemie * patologie MeSH
- antitumorózní látky * terapeutické užití MeSH
- interferon typ I * MeSH
- lidé MeSH
- nádorové mikroprostředí MeSH
- signální transdukce MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Dendritic cells (DCs) have received considerable attention as potential targets for the development of novel cancer immunotherapies. However, the clinical efficacy of DC-based vaccines remains suboptimal, largely reflecting local and systemic immunosuppression at baseline. An autologous DC-based vaccine (DCVAC) has recently been shown to improve progression-free survival and overall survival in randomized clinical trials enrolling patients with lung cancer (SLU01, NCT02470468) or ovarian carcinoma (SOV01, NCT02107937), but not metastatic castration-resistant prostate cancer (SP005, NCT02111577), despite a good safety profile across all cohorts. We performed biomolecular and cytofluorometric analyses on peripheral blood samples collected prior to immunotherapy from 1000 patients enrolled in these trials, with the objective of identifying immunological biomarkers that may improve the clinical management of DCVAC-treated patients. Gene signatures reflecting adaptive immunity and T cell activation were associated with favorable disease outcomes and responses to DCVAC in patients with prostate and lung cancer, but not ovarian carcinoma. By contrast, the clinical benefits of DCVAC were more pronounced among patients with ovarian carcinoma exhibiting reduced expression of T cell-associated genes, especially those linked to TH2-like signature and immunosuppressive regulatory T (TREG) cells. Clinical responses to DCVAC were accompanied by signs of antitumor immunity in the peripheral blood. Our findings suggest that circulating signatures of antitumor immunity may provide a useful tool for monitoring the potency of autologous DC-based immunotherapy.
- MeSH
- dendritické buňky metabolismus MeSH
- epiteliální ovariální karcinom farmakoterapie MeSH
- lidé MeSH
- nádory plic * farmakoterapie terapie MeSH
- nádory vaječníků * genetika terapie MeSH
- protinádorové vakcíny * terapeutické užití MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
PURPOSE: The successful implementation of immune checkpoint inhibitors (ICI) in the clinical management of various solid tumors has raised considerable expectations for patients with epithelial ovarian carcinoma (EOC). However, EOC is poorly responsive to ICIs due to immunologic features including limited tumor mutational burden (TMB) and poor lymphocytic infiltration. An autologous dendritic cell (DC)-based vaccine (DCVAC) has recently been shown to be safe and to significantly improve progression-free survival (PFS) in a randomized phase II clinical trial enrolling patients with EOC (SOV01, NCT02107937). PATIENTS AND METHODS: We harnessed sequencing, flow cytometry, multispectral immunofluorescence microscopy, and IHC to analyze (pretreatment) tumor and (pretreatment and posttreatment) peripheral blood samples from 82 patients enrolled in SOV01, with the aim of identifying immunologic biomarkers that would improve the clinical management of patients with EOC treated with DCVAC. RESULTS: Although higher-than-median TMB and abundant CD8+ T-cell infiltration were associated with superior clinical benefits in patients with EOC receiving standard-of-care chemotherapy, the same did not hold true in women receiving DCVAC. Conversely, superior clinical responses to DCVAC were observed in patients with lower-than-median TMB and scarce CD8+ T-cell infiltration. Such responses were accompanied by signs of improved effector functions and tumor-specific cytotoxicity in the peripheral blood. CONCLUSIONS: Our findings suggest that while patients with highly infiltrated, "hot" EOCs benefit from chemotherapy, women with "cold" EOCs may instead require DC-based vaccination to jumpstart clinically relevant anticancer immune responses.
- MeSH
- dendritické buňky MeSH
- epiteliální ovariální karcinom * genetika terapie MeSH
- lidé MeSH
- mutace MeSH
- nádorové biomarkery MeSH
- nádory vaječníků * genetika terapie MeSH
- protinádorové vakcíny * terapeutické užití MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
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.
BACKGROUND: The immunological microenvironment of primary high-grade serous carcinomas (HGSCs) has a major impact on disease outcome. Conversely, little is known on the microenvironment of metastatic HGSCs and its potential influence on patient survival. Here, we explore the clinical relevance of the immunological configuration of HGSC metastases. METHODS: RNA sequencing was employed on 24 paired primary tumor microenvironment (P-TME) and metastatic tumor microenvironment (M-TME) chemotherapy-naive HGSC samples. Immunohistochemistry was used to evaluate infiltration by CD8+ T cells, CD20+ B cells, DC-LAMP+ (lysosomal-associated membrane protein 3) dendritic cells (DCs), NKp46+ (natural killer) cells and CD68+CD163+ M2-like tumor-associated macrophages (TAMs), abundance of PD-1+ (programmed cell death 1), LAG-3+ (lymphocyte-activating gene 3) cells, and PD-L1 (programmed death ligand 1) expression in 80 samples. Flow cytometry was used for functional assessments on freshly resected HGSC samples. RESULTS: 1468 genes were differentially expressed in the P-TME versus M-TME of HGSCs, the latter displaying signatures of extracellular matrix remodeling and immune infiltration. M-TME infiltration by immune effector cells had little impact on patient survival. Accordingly, M-TME-infiltrating T cells were functionally impaired, but not upon checkpoint activation. Conversely, cytokine signaling in favor of M2-like TAMs activity appeared to underlie inhibited immunity in the M-TME and poor disease outcome. CONCLUSIONS: Immunosuppressive M2-like TAM infiltrating metastatic sites limit clinically relevant immune responses against HGSCs.
- MeSH
- imunosupresivní léčba metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- makrofágy imunologie MeSH
- metastázy nádorů MeSH
- nádorové biomarkery metabolismus MeSH
- nádorové mikroprostředí MeSH
- nádory vaječníků imunologie MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Natural killer (NK) cells constitute the predominant innate lymphocyte subset that mediates the anti-viral and anti-tumor immune responses. NK cells use an array of innate receptors to sense their environment and to respond to infections, cellular stress and transformation. The resulting NK cell activation, including cytotoxicity and cytokine production, is a fundamental component of the early immune response. The most recent discoveries in NK cell biology have stimulated the translational research that has led to remarkable results for the treatment of human malignancies. Therefore, the rapid isolation of NK cells from the peripheral blood or tumor microenvironment and the subsequent assessment of cytolytic function are crucial to the study of their potency and NK cell-mediated immunosurveillance. Here, we provide protocols for NK cell isolation and the assessment of NK cell cytotoxicity using flow cytometry.
Aim: To identify coping strategies nurses working in clinical practice use to manage workload, and, subsequently, to determine whether the choice of coping strategies is related to self-esteem. Design: Quantitative cross-sectional study. Methods: The sample consisted of 509 nurses. Two coping strategies questionnaires – Brief COPE and Rosenberg Self-Esteem Scale – RSES were used to collect data. The data were evaluated by descriptive statistical methods and analysed via ANOVA. Results: Nurses prefer to adopt a range of adaptive coping strategies rather than maladaptive coping strategies. The most frequently chosen adaptive coping strategies used by nurses in clinical practice are acceptance, planning, and active coping. We found that selection of coping strategies is closely related to self-esteem. We registered a significant difference in preferences for adaptive and maladaptive coping strategies as follows: nurses with high self-esteem scores (RSES) preferred adaptive coping strategies: active coping (p = 0.017), positive reframing (p = 0.001), planning (p = 0.020), and acceptance (p = 0.045). We identified selection of maladaptive coping strategies in nurses with average and low self-esteem scale results, i.e.: denial (p = 0.000), disengaged behaviour (p = 0.001), and self-blaming (p = 0.000). Conclusion: The results of the study suggest that it is important to support nurses’ self-esteem since this influences choice of adaptive coping strategies. These are an effective means of coping with the burden on nurses, which directly affects the quality of nursing care provided to patients in clinical practice.
Úvod: Cieľom výskumu bolo zhodnotiť faktory psychickej pracovnej záťaže sestier a zistiť, či dĺžka praxe má vplyv na ich psychickú zaťaž. Sledované bolo aj subjektívne vyjadrenie sestier vo vzťahu k psychickej pracovnej záťaži. Súbor a metodika: Súbor tvorilo 279 sestier pracujúcich na psychiatrických pracoviskách na Slovensku. Na hodnotenie psychickej pracovnej záťaže bol použitý Meisterov dotazník. Dáta boli spracované štatistickým programom SPSS 21.0 a interpretované prostredníctvom metód deskriptívnej a induktívnej štatistiky. Výsledky: U sestier sa celkovo preukázal 2. stupeň psychickej pracovnej záťaže. Prekročenie kritických hodnôt mediánu bolo identifikované v položkách: časová tieseň, vysoká zodpovednosť, únava a dlhodobá únosnosť. V komparácii s populačnou normou boli u sestier prekročené kritické hodnoty vo faktore I. Preťaženie. Štatisticky signifikantný vzťah medzi dĺžkou praxe a psychickou pracovnou záťažou sestier nebol potvrdený. Záver: Zvýšená psychická pracovná záťaž môže negatívne pôsobiť na zdravie a pracovnú výkonnosť sestry. V súvislosti so záťažou je potrebné špecifikovať účinné preventívne odporúčania pre zamestnancov a zamestnávateľov, ktorú budú nasmerované k minimalizácii výskytu chorôb z povolania a zlepšeniu pracovných podmienok.
Introduction: The investigation evaluated factors of mental workload for nurses and the role of experience duration there. The authors also followed subjective evaluation of the nurses in relation to the mental workload. The group and methods: The group involved 279 nurses working at the workplaces of psychiatry in Slovakia. The evaluation of mental workload employed the Meister's questionnaire. The data were processed by the statistical program SPSS 21.0 ad interpreted by methods of descriptive and inductive statistics. Results: the nurses were exposed to 2nd degree of mental workload. The critical median values were identified as exceeded in the following items: time pressure, high responsibility, fatigue and long-term tolerability. In comparison with the population standard the critical values were exceeded in factor Overload I. Statistically significant relation between the duration of practice and mental workload of the nurses was not confirmed. Conclusion: Increased mental workload may negatively influence health and working performance of the nurses. It is necessary to specify effective preventive recommendations for the employees and employers, which would be directed to minimization of occupational diseases incidence and improvement of working conditions.
- MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- pracovní zátěž * psychologie MeSH
- průzkumy a dotazníky MeSH
- psychiatrické oddělení nemocnice MeSH
- psychický stres MeSH
- zdravotní sestry v klinické praxi * psychologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Geografické názvy
- Slovenská republika MeSH
PURPOSE: In multiple oncological settings, expression of the coinhibitory ligand PD-L1 by malignant cells and tumor infiltration by immune cells expressing coinhibitory receptors such as PD-1, CTLA4, LAG-3, or TIM-3 conveys prognostic or predictive information. Conversely, the impact of these features of the tumor microenvironment on disease outcome among high-grade serous carcinoma (HGSC) patients remains controversial. EXPERIMENTAL DESIGN: We harnessed a retrospective cohort of 80 chemotherapy-naïve HGSC patients to investigate PD-L1 expression and tumor infiltration by CD8+ T cells, CD20+ B cells, DC-LAMP+ dendritic cells as well as by PD-1+, CTLA4+, LAG-3+, and TIM-3+ cells in relation with prognosis and function orientation of the tumor microenvironment. IHC data were complemented with transcriptomic and functional studies on a second prospective cohort of freshly resected HGSC samples. In silico analysis of publicly available RNA expression data from 308 HGSC samples was used as a confirmatory approach. RESULTS: High levels of PD-L1 and high densities of PD-1+ cells in the microenvironment of HGSCs were strongly associated with an immune contexture characterized by a robust TH1 polarization and cytotoxic orientation that enabled superior clinical benefits. Moreover, PD-1+TIM-3+CD8+ T cells presented all features of functional exhaustion and correlated with poor disease outcome. However, although PD-L1 levels and tumor infiltration by TIM-3+ cells improved patient stratification based on the intratumoral abundance of CD8+ T cells, the amount of PD-1+ cells failed to do so. CONCLUSIONS: Our data indicate that PD-L1 and TIM-3 constitute prognostically relevant biomarkers of active and suppressed immune responses against HGSC, respectively.
- MeSH
- antigen CTLA-4 imunologie metabolismus MeSH
- antigeny CD274 imunologie metabolismus MeSH
- buněčný receptor 2 viru hepatitidy A imunologie metabolismus MeSH
- CD8-pozitivní T-lymfocyty imunologie MeSH
- dospělí MeSH
- epiteliální ovariální karcinom imunologie metabolismus patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- membránové glykoproteiny asociované s lyzozomy imunologie metabolismus MeSH
- míra přežití MeSH
- nádorové biomarkery imunologie metabolismus MeSH
- nádorové proteiny imunologie metabolismus MeSH
- prognóza MeSH
- regulace genové exprese u nádorů * MeSH
- retrospektivní studie MeSH
- senioři MeSH
- serózní cystadenokarcinom imunologie metabolismus patologie MeSH
- tumor infiltrující lymfocyty imunologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
