Major histocompatibility complex class I-specific inhibitory receptors on
natural killer cells prevent the lysis of healthy autologous cells. The outcome
of this negative signal is not anergy or ...apoptosis of natural killer cells but
a transient abortion of activation signals. The natural killer inhibitory
receptors fulfill this function by recruiting the tyrosine phosphatase SHP-1
through a cytoplasmic immunoreceptor tyrosine-based inhibition motif. This
immunoreceptor tyrosine-based inhibition motif has become the hallmark of a
growing family of receptors with inhibitory potential, which are expressed in
various cell types such as monocytes, macrophages, dendritic cells, leukocytes,
and mast cells. Most of the natural killer inhibitory receptors and two members
of a monocyte inhibitory-receptor family bind major histocompatibility complex
class I molecules. Ligands for many of the other receptors have yet to be
identified. The inhibitory-receptor superfamily appears to regulate many types
of immune responses by blocking cellular activation signals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Natural killer (NK) cells possess potent cytolytic activity and secrete immune modulating cytokines. The large repertoire of NK cell receptors provides versatility for the identification of infected ...and transformed cells and for their elimination by NK cells. NK cell responses also stimulate and regulate the adaptive arm of the immune system. We review current knowledge about the molecular specificity of NK cell receptors and about the regulation of NK cell effector functions upon encounter with target cells. Mechanisms of recognition, interplay among receptors, signal integration, and the dynamic fine-tuning of NK cell responses are discussed. New insights into the molecular checkpoints for NK cell effector function are highlighted, and underlying reasons for the complexity in NK cell recognition and signaling are proposed.
Cytotoxic lymphocytes kill target cells by releasing the content of secretory lysosomes at the immune synapse. To understand the dynamics and control of cytotoxic immune synapses, we imaged human ...primary, live natural killer cells on lipid bilayers carrying ligands of activation receptors. Formation of an organized synapse was dependent on the presence of the β2 integrin ligand ICAM-1. Ligands of coactivation receptors 2B4 and NKG2D segregated into central and peripheral regions, respectively. Lysosomal protein LAMP-1 that was exocytosed during degranulation accumulated in a large and spatially stable cluster, which overlapped with a site of membrane internalization. Lysosomal compartments reached the plasma membrane at focal points adjacent to centrally accumulated LAMP-1. Imaging of fixed cells revealed that perforin-containing granules were juxtaposed to an intracellular compartment where exocytosed LAMP-1 was retrieved. Thus, cytotoxic immune synapses include a central region of bidirectional vesicular traffic, which is controlled by integrin signaling.
Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the ...Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-lymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS.
Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry.
There was strong interobserver reproducibility in assessment of pathological response (κ = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P = 0.008) and prolonged RFS (P = 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had ≥70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P = 0.002 and P ≤ 0.0001). The number of B lymphocytes was significantly increased in patients with a high fibrosis subtype of treatment response (P = 0.046).
There is strong reproducibility for assessment of pathological response using INMC criteria. Immunotherapeutic response of fibrosis subtype correlated with improved RFS, and may represent a biomarker. Potential B-cell contribution to fibrosis development warrants further study. Reclassification of pNR to a threshold of ≥70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation.
•Eighty-three lymph node dissections following neoadjuvant immunotherapy for stage III metastatic melanoma were assessed.•There was strong reproducibility in assessment of INMC pathological response category and percentage of viable melanoma.•High fibrosis was associated with a lack of recurrence and increased RFS, representing a possible biomarker.•Two different scoring systems of response were assessed and both scoring systems correlated with a lack of recurrence.•High fibrosis was also associated with increased levels of B cells within the tumour bed.
IMPORTANCEHypertensive pregnancy disorders (HPDs) are associated with an increased risk of long-term cardiovascular disease. Speckle tracking echocardiography (STE) might be useful in the early ...detection of preclinical cardiac changes in women with HPDs.
OBJECTIVEThe aim of this study was to study whether STE is a suitable method to detect differences in cardiac function in pregnant women with HPD compared with normotensive pregnant women or between women with a history of a pregnancy complicated by HPD compared with women with a history of an uncomplicated pregnancy.
EVIDENCE ACQUISITIONThe databases Medline, EMBASE, and Central were systematically searched for studies comparing cardiac function measured with STE in pregnant women with HPD or women with a history of HPD and women with a history of normotensive pregnancies.
RESULTSThe search identified 16 studies, including 870 women with a history of HPD and 693 normotensive controls. Most studies during pregnancy (n = 12/13) found a decreased LV-GLS (left ventricular global longitudinal strain) in HPD compared with normotensive pregnant controls. LV-GRS (left ventricular global radial strain) and LV-GLCS (left ventricular global circumferential strain) are decreased in women with early-onset and severe preeclampsia. Women with a history of early-onset preeclampsia show lasting myocardial changes, with significantly decreased LV-GLS, LV-GLCS, and LV-GRS.
CONCLUSIONS AND RELEVANCELV-GLS is significantly decreased in pregnant women with HPD compared with normotensive pregnant women. Other deformation values show a significant decrease in women with severe or early-onset preeclampsia, with lasting myocardial changes after early-onset preeclampsia.
TARGET AUDIENCEObstetricians and gynecologists, family physicians, cardiologists.
LEARNING OBJECTIVESAfter participating in this activity, the learner should be better able to identify the test characteristics of STE; describe the differences in STE between HPDs and normotensive pregnant controls; and explain which HPD causes lasting myocardial changes after pregnancy.
Human natural killer (NK) cells express several killer cell immunoglobulin (Ig)-like receptors (KIRs) that inhibit their cytotoxicity upon recognition of human histocompatibility leukocyte antigen ...(HLA) class I molecules on target cells. Additional members of the KIR family, including some that deliver activation signals, have unknown ligand specificity and function. One such KIR, denoted KIR2DL4, is structurally divergent from other KIRs in the configuration of its two extracellular Ig domains and of its transmembrane and cytoplasmic domains. Here we show that recombinant soluble KIR2DL4 binds to cells expressing HLA-G but not to cells expressing other HLA class I molecules. Unlike other HLA class I-specific KIRs, which are clonally distributed on NK cells, KIR2DL4 is expressed at the surface of all NK cells. Furthermore, functional transfer of KIR2DL4 into the cell line NK-92 resulted in inhibition of lysis of target cells that express HLA-G, but not target cells that express other class I molecules including HLA-E. Therefore, given that HLA-G expression is restricted to fetal trophoblast cells, KIR2DL4 may provide important signals to maternal NK decidual cells that interact with trophoblast cells at the maternal-fetal interface during pregnancy.
Activated NK cells lyse tumor cells and virus-infected cells and produce IFN-gamma upon contact with sensitive target cells. The regulation of these effector responses in resting NK cells is not well ...understood. We now describe a receptor, KIR2DL4, that has the unique property of inducing IFN-gamma production, but not cytotoxicity, by resting NK cells in the absence of cytokines. In contrast, the NK cell-activation receptors CD16 and 2B4 induced cytotoxicity but not IFN-gamma production. The induction by KIR2DL4 of IFN-gamma production by resting NK cells was blocked by an inhibitor of the p38 mitogen-activated protein kinase signaling pathway, in contrast to the IL-2-induced IFN-gamma secretion that was sensitive to inhibition of the extracellular signal-regulated kinase mitogen-activated protein kinase pathway. These results reveal a functional dichotomy (cytokine production vs cytotoxicity) in the response of resting NK cells, as dictated by the signals of individual receptors.
KIR2DL4 (CD158d) is an unusual member of the killer cell Ig-like receptor family expressed in all NK cells and some T cells. KIR2DL4 activates the cytotoxicity of NK cells, despite the presence of an ...immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic tail. The role of this ITIM on the activating function of KIR2DL4, and whether it can provide inhibitory signals, is not known. Mutated forms of KIR2DL4 were engineered that lacked either the tyrosine in the ITIM or an arginine-tyrosine motif in the transmembrane region that is required for the activation signal. The activity of the mutated KIR2DL4 molecules was tested in a redirected lysis assay. The ITIM was not necessary for activation of lysis by KIR2DL4. The activation signal of KIR2DL4 was sensitive to inhibition by another ITIM-containing receptor. The activation-deficient mutant of KIR2DL4 inhibited the signal delivered by the activating receptor CD16. In pull-down experiments with GST fusion proteins, the tyrosine-phosphorylated cytoplasmic tail of KIR2DL4 bound the Src homology 2-containing phosphatases 1 and 2, as did the tail of the inhibitory receptor KIR2DL1. Therefore, KIR2DL4 has inhibitory potential in addition to its activating function.
Background
Identifying patients with sentinel node‐negative melanoma at high risk of recurrence or death is important. The European Organisation for Research and Treatment of Cancer (EORTC) recently ...developed a prognostic model including Breslow thickness, ulceration and site of the primary tumour. The aims of the present study were to validate this prognostic model externally and to assess whether it could be improved by adding other prognostic factors.
Methods
Patients with sentinel node‐negative cutaneous melanoma were included in this retrospective single‐institution study. The β values of the EORTC prognostic model were used to predict recurrence‐free survival and melanoma‐specific survival. The predictive performance was assessed by discrimination (c‐index) and calibration. Seeking to improve the performance of the model, additional variables were added to a Cox proportional hazards model.
Results
Some 4235 patients with sentinel node‐negative cutaneous melanoma were included. The median follow‐up time was 50 (i.q.r. 18·5–81·5) months. Recurrences and deaths from melanoma numbered 793 (18·7 per cent) and 456 (10·8 per cent) respectively. Validation of the EORTC model showed good calibration for both outcomes, and a c‐index of 0·69. The c‐index was only marginally improved to 0·71 when other significant prognostic factors (sex, age, tumour type, mitotic rate) were added.
Conclusion
This study validated the EORTC prognostic model for recurrence‐free and melanoma‐specific survival of patients with negative sentinel nodes. The addition of other prognostic factors only improved the model marginally. The validated EORTC model could be used for personalizing follow‐up and selecting high‐risk patients for trials of adjuvant systemic therapy.
Antecedentes
Es importante identificar a los pacientes con melanoma y ganglio centinela negativo con alto riesgo de recidiva o muerte. Con este fin, la European Organisation for Research and Treatment of Cancer (EORTC) ha desarrollado recientemente un modelo pronóstico que incluye el índice de Breslow, la presencia de úlcera y la localización del tumor primario. Los objetivos del presente estudio fueron efectuar la validación externa de este modelo pronóstico y evaluar si pudiera mejorarse agregando otros factores pronósticos.
Métodos
Estudio retrospectivo de una sola institución, en el que se incluyeron 4.235 pacientes con melanoma cutáneo y ganglio centinela negativo. La mediana de seguimiento fue de 50 meses (rango intercuartílico 18,5‐81,5). Para predecir la supervivencia sin recidiva y la supervivencia específica para el melanoma se utilizaron los valores beta del modelo de pronóstico de la EORTC. La capacidad predictiva se evaluó mediante los índices de discriminación (índice c) y de calibración. Para mejorar el rendimiento de este modelo, se agregaron más variables utilizando un modelo de riesgos proporcionales de Cox.
Resultados
Las recidivas y muertes por melanoma fueron 793 (19%) y 456 (11%), respectivamente. La validación del modelo EORTC mostró una buena calibración para ambos resultados y un índice c de 0,69. El índice c sólo mejoró marginalmente a 0,71 cuando se agregaron otros factores pronósticos significativos (género, edad, tipo de tumor, índice mitótico).
Conclusión
La validación externa del modelo de pronóstico EORTC para la supervivencia sin recidiva y específica en pacientes con melanoma y ganglio centinela negativo fue satisfactoria. La adición de otros factores pronósticos solo mejoró marginalmente el modelo. El modelo validado de la EORTC podría utilizarse para personalizar las estrategias de seguimiento y seleccionar a pacientes de alto riesgo para ensayos con terapia sistémica adyuvante.
In this study a prognostic model to predict survival of sentinel node‐negative melanoma patients was successfully validated. It could be used for personalizing follow‐up regimens and selecting high‐risk patients for trials of adjuvant systemic therapy.
Validated
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