126 research outputs found
Natural killer cells and neuroblastoma: Tumor recognition, escape mechanisms, and possible novel immunotherapeutic approaches
No full textNeuroblastoma (NB) is the most common extra-cranial solid tumor of childhood and arises from developing sympathetic nervous system. Most primary tumors localize in the abdomen, the adrenal gland, or lumbar sympathetic ganglia. Amplification in tumor cells of MYCN, the major oncogenic driver, patients' age over 18 months, and the presence at diagnosis of a metastatic disease (stage IV, M) identify NB at high risk of treatment failure. Conventional therapies did not significantly improve the overall survival of these patients. Moreover, the limited landscape of somatic mutations detected in NB is hampering the development of novel pharmacological approaches. Major efforts aim to identify novel NB-associated surface molecules that activate immune responses and/or direct drugs to tumor cells and tumor-associated vessels. PVR (Poliovirus Receptor) and B7-H3 are promising targets, since they are expressed by most high-risk NB, are upregulated in tumor vasculature and are essential for tumor survival/invasiveness. PVR is a ligand of DNAM-1 activating receptor that triggers the cytolytic activity of natural killer (NK) cells against NB. In animal models, targeting of PVR with an attenuated oncolytic poliovirus induced tumor regression and elimination. Also B7-H3 was successfully targeted in preclinical studies and is now being tested in phase I/II clinical trials. B7-H3 down-regulates NK cytotoxicity, providing NB with a mechanism of escape from immune response. The immunosuppressive potential of NB can be enhanced by the release of soluble factors that impair NK cell function and/or recruitment. Among these, TGF-β1 modulates the cytotoxicity receptors and the chemokine receptor repertoire of NK cells. Here, we summarize the current knowledge on the main cell surface molecules and soluble mediators that modulate the function of NK cells in NB, considering the pros and cons that must be taken into account in the design of novel NK cell-based immunotherapeutic approaches. © 2014 Bottino, Dondero, Bellora, Moretta, Locatelli, Pistoia, Moretta and Castriconi
The leukocyte Ig-like receptor (LIR)-1 for the Cytomegalovirus UL18 protein displays a broad specificity for different HLA class I alleles: analysis of LIR-1+ NK cell clones
No full textM-CSF induces the expression of a membrane-bound form of IL-18 in a subset of human monocytes differentiating in vitro toward macrophages
No full textIL-18 is a proinflammatory cytokine belonging to the "IL-1 family" that has been shown to play a prominent role in the induction of type 1 immune responses. Here, we show that M-CSFinduces the expression of a membrane-bound form of IL-18 (mIL-18) in a subset of human blood monocytes differentiating toward macrophages. While monocytes, DC, and GM-CSF-treated monocytes did not express mIL-18, its expression was detected in approximately 30-40% of M-CSF-primed macrophages differentiating from both CD16(-) and CD16(+) monocytes. Treatment with the caspase-1 inhibitor significantly reduced mIL-18 expression suggesting the requirement of an assembled inflammasome for IL-18 surface expression. Polarization toward M2 did not modify mIL-18 expression. On the contrary, LPS stimulation of both M0 and M2 (mIL-18(+) ) macrophages induced shedding of mIL-18, which was likely mediated by the activation of cellular protease(s). Importantly, the soluble form IL-18 (sIL-18) induced in autologous resting NK cells both the expression of CCR7 and the production of high amounts of IFN-γ, which was virtually abrogated by Ab-mediated neutralization of sIL-18. Overall our data shed new light on the cells and mechanisms leading to the release of sIL-18, the major IFN-γ-inducing factor in both physiological and pathological immune responses
The LIR-1 receptor for the cytomegalovirus UL18 protein displays a broad specificity for different HLA class I alleles.
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Volume dose distribution in digital breast tomosynthesis: A phantom study
No full textMonte Carlo calculations for breast dosimetry in Digital Breast Tomosynthesis (DBT) may require experimental validations, e.g. via the assessment of the calculated and measured dose volume distribution in the breast. This might also take into account any uneven distribution of the beam intensity in the entrance plane, not usually considered in Monte Carlo simulations, e.g. as determined by the heel effect. We measured the 3D dose distribution in a breast phantom, using XR-QA2 radiochromic films calibrated in free-in-air air kerma. Film sheets were positioned at the entrance surface, at the bottom surface as well as at four depths between adjacent slabs in the 5-slabs, 5-cm-thick phantom simulating a compressed breast with 50% glandular fraction. By varying the irradiation angle, the basic requirements of a DBT scan were simulated. The irradiations were made at 40 kV (HVL 1.1 mm Al) for three angular positions of the beam central axis (θ = ±25 deg and θ = 0 deg normal incidence, simulating a craniocaudal view). Results show that it is possible to determine the transverse and longitudinal distribution of the average dose in the phantom (in terms of kerma in simulated breast tissue 50/50 normalized to the entrance kerma), showing the angular dependence of the depth-resolved dose. In the direction of the beam axis, the dose decreases down to about 26% of the entrance value without the phantom. The backscatter fraction was 8%. In transverse planes the maximum dose variations are between 6% and 18% at θ = 0 deg, whereas the dose varies up to 22% in angular views
The AZ158 mAb specifically reacts with p70 and p140 inhibitory NK receptors for HLA-B and HLA-A alleles
No full textAnalysis of the molecular mechanism involved in 2B4-mediated NK cell activation: evidence that human 2B4 is physically and functionally associated with the linker for activation of T cells
No full textDose Volume Distribution in Digital Breast Tomosynthesis: A Phantom Study
No full textMonte Carlo (MC) calculations for breast dosimetry in digital breast tomosynthesis (DBT) require experimental validations. We measured the 3-D dose distribution in breast phantoms, using XR-QA2 radiochromic films, compared to dose maps obtained with a previously validated MC code. Film sheets were positioned at the entrance surface, at the bottom surface as well as at four depths between adjacent slabs in the five-slabs 50-mm-thick phantoms simulating a compressed breast. We employed a homogeneous PMMA phantom, for the method validation, and a heterogeneous (BR 50/50) phantom for a preliminary study in a complex breast phantom. Irradiations were made at 40 kV at ±25° and 0° in craniocaudal view. A continuous scan over 15° was carried out for the homogeneous phantom. In the direction of the beam axis the dose decreases down to 12% of the entrance value. In the transverse planes, the dose varies up to 17%; in the heterogeneous phantom, it decreases to 25% in the direction of the beam axis. In transverse planes the maximum dose variations are up to 18% at θ = 0°, whereas the dose varies up to 22% in angular views. The simulations agreed with the measured values within the measurement uncertainties
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