In this review, we overview the main features and functions of NK cells, focusing on their role in cell-mediated immune response to tumor cells. In parallel, we discuss the information available in the field of NK cell receptors and offer a wide general overview of functional aspects of cell targeting and killing, focusing on the recent acknowledgments on the efficacy of NK cells after cytokine and mAb administration in cancer therapy. Since efficacy of NK cell-based immunotherapy has been proven in KIR-mismatch regimens or in TRAIL-dependent apoptosis, the ability to manipulate the balance of activating and inhibitory receptors on NK cells and of their cognate ligands, as well as the sensitivity of tumor cells to apoptosis, opens new perspectives for NK cell-based immunotherapy.
Activated ALK and ROS1 tyrosine kinases, resulting from chromosomal rearrangements, occur in a subset of non-small cell lung cancers (NSCLC) as well as other tumor types and their oncogenic relevance as actionable targets has been demonstrated by the efficacy of selective kinase inhibitors such as crizotinib, ceritinib, and alectinib. More recently, low-frequency rearrangements of TRK kinases have been described in NSCLC, colorectal carcinoma, glioblastoma, and Spitzoid melanoma. Entrectinib, whose discovery and preclinical characterization are reported herein, is a novel, potent inhibitor of ALK, ROS1, and, importantly, of TRK family kinases, which shows promise for therapy of tumors bearing oncogenic forms of these proteins. Proliferation profiling against over 200 human tumor cell lines revealed that entrectinib is exquisitely potent in vitro against lines that are dependent on the drug's pharmacologic targets. Oral administration of entrectinib to tumor-bearing mice induced regression in relevant human xenograft tumors, including the TRKA-dependent colorectal carcinoma KM12, ROS1-driven tumors, and several ALK-dependent models of different tissue origins, including a model of brain-localized lung cancer metastasis. Entrectinib is currently showing great promise in phase I/II clinical trials, including the first documented objective responses to a TRK inhibitor in colorectal carcinoma and in NSCLC. The drug is, thus, potentially suited to the therapy of several molecularly defined cancer settings, especially that of TRK-dependent tumors, for which no approved drugs are currently available.
The expression of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors was investigated in resting and cytokine-activated purified primary human natural killer (NK) and CD8 ؉ T cells. Resting NK and CD8 ؉ T cells expressed the mRNA for all TRAIL receptors, but TRAIL-R4 was the only receptor clearly detectable on the surface of both cell types. NK cells were activated by interleukin 2 (IL-2) or IL-15, whereas CD8 ؉ T cells were activated by phytohemagglutinin (PHA) ؉ IL-2 followed by IL-2 alone for up to 10 days. On activation, both cell types rapidly expressed TRAIL-R2 and TRAIL-R3, whose expression peaked at day 10 of culture. TRAIL-R1, however, was never expressed at any time point examined, whereas the expression of TRAIL-R4, which showed a progressive increase in CD8
Growth Factor Receptor. NTRK1 was originally isolated from a colorectal carcinoma (CRC) sample as component of a somatic rearrangement (TPM3-NTRK1) resulting in expression of the oncogenic chimeric protein TPM3-TRKA, but there has been no subsequent report regarding the relevance of this oncogene in CRC. The KM12 human CRC cell line expresses the chimeric TPM3-TRKA protein and is hypersensitive to TRKA kinase inhibition.We report the detailed characterization of the TPM3-NTRK1 genomic rearrangement in KM12 cells and through a cellular screening approach, the identification of NMS-P626, a novel highly potent and selective TRKA inhibitor. NMS-P626 suppressed TPM3-TRKA phosphorylation and downstream signaling in KM12 cells and showed remarkable antitumor activity in mice bearing KM12 tumors.Finally, using quantitative reverse transcriptase PCR and immunohistochemistry (IHC) we identified the TPM3-NTRK1 rearrangement in a CRC clinical sample, therefore suggesting that this chromosomal translocation is indeed a low frequency recurring event in CRC and that such patients might benefit from therapy with TRKA kinase inhibitors.
Inflammation generates various changes in body iron homeostasis, including iron sequestration in the reticuloendothelial system with ensuing hypoferremia and anemia of chronic disease. Increased iron accumulation is caused by hepcidin-mediated down-regulation of the iron export protein ferroportin and higher iron uptake. However, enhanced iron acquisition by macrophages cannot be accounted for by the previously reported transferrin receptor (TfR1) down-regulation in macrophages exposed to lipopolysaccharide (LPS)/interferon ␥ (IFN␥) because it impairs a major iron uptake mechanism. Because TfR1 is up-regulated by the hypoxia-inducible factor (HIF-1), we investigated the effect of inflammatory and anti-inflammatory signals on HIF-1-mediated TfR1 gene expression. Inflammatory states are associated with changes in body iron homeostasis (1). The main systemic response is a rapid fall in plasma iron concentration accompanied by iron sequestration in the reticuloendothelial system. By restricting iron availability for erythroid progenitor cells, prolonged hypoferremia may limit hemoglobin synthesis and cause inflammation-related anemia (2, 3). Increased iron retention within inflammatory macrophages, which is favored by the induction of the iron storage protein ferritin (4 -8) and regarded as a host attempt to withhold iron from the invading pathogens (1, 9, 10), may be due to increased iron uptake and decreased iron export (9). Characterization of the interaction between the acute phase protein hepcidin and the iron exporter ferroportin has shed light on the molecular mechanisms underlying the blockade of macrophage iron release (2, 3, 11). The cytokine-triggered increase in circulating hepcidin causes the internalization and degradation of ferroportin (12), the major iron exporter, thus blocking iron release from macrophages (13). However, although it has been shown that direct exposure to a bolus of hepcidin rapidly lowers serum iron (14) and that peak urinary hepcidin levels in LPS-treated subjects precede the development of hypoferremia (15), the rapid onset of hypoferremia in LPS-treated mice (16 -19) suggests that factors other than hepcidin-dependent ferroportin down-regulation (e.g. iron uptake) may be important for iron sequestration within reticuloendothelial cells during the very early phase of the inflammatory response.The pathways of iron acquisition by macrophages are less clear, as are the changes induced by inflammatory stimuli. This is particularly true in the case of the role of changes in the internalization of transferrin-bound iron through the transferrin receptor (TfR1) 2 during the development of reticuloendothelial iron sequestration under inflammatory conditions. A number of studies have shown that exposure to inflammatory stimuli for 10 -24 h down-regulates TfR1 expression (5, 6, 20 -23) and, because this impairs a major iron uptake mechanism (21, 23), it cannot account for the increased accumulation of iron in macrophages. This inhibition of TfR1 expression is post-transcriptionally control...
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