NKG2D/NKG2-Ligand Pathway Offers New Opportunities in Cancer Treatment

The antitumor functions of NK cells are regulated by the integration of positive and negative signals triggered by numerous membrane receptors present on the NK cells themselves. Among the main activating receptors, NKG2D binds several stress-induced molecules on tumor targets. Engagement of NKG2D by its ligands (NKG2D-Ls) induces NK cell activation leading to production of cytokines and target cell lysis. These effects have therapeutic potential as NKG2D-Ls are widely expressed by solid tumors, whereas their expression in healthy cells is limited. Here, we describe the genetic and environmental factors regulating the NKG2D/NKG2D-L pathway in tumors. NKG2D-L expression is linked to cellular stress and cell proliferation, and has been associated with oncogenic mutations. Tumors have been found to alter their to NKG2D-L expression as they progress, which interferes with the antitumor function of the pathway. Nevertheless, this pathway could be advantageously exploited for cancer therapy. Various cancer treatments, including chemotherapy and targeted therapies, indirectly interfere with the cellular and soluble forms of NKG2D-Ls. In addition, NKG2D introduced into chimeric antigen receptors in T- and NK cells is a promising tumor immunotherapy approach

Modulation of NK cell activation by exogenous calcium from alginate dressings in vitro

Natural Killer (NK) cells participate in the defense against infection by killing pathogens and infected cells and secreting immuno-modulatory cytokines. Defects in NK cell activity have been reported in obese, diabetic, and elderly patients that are at high risk of developing infected chronic wounds. Calcium alginate dressings are indicated for the debridement during the inflammatory phase of healing. Since calcium ions are major activators of NK cells, we hypothesized that these dressings could enhance NK functions, as investigated in vitro herein. Primary human blood NK cells were freshly-isolated from healthy volunteers and exposed to conditioned media (CM) from two alginate dressings, Algosteril® (ALG, pure Ca2+ alginate) and Biatain® Alginate (BIA, Ca2+ alginate with CMC), in comparison with an exogenous 3mM calcium solution. Our results demonstrated that exogenous calcium and ALG-CM, but not BIA-CM, induced NK cell activation and enhanced their capacity to kill their targets as a result of increased degranulation. NK cell stimulation by ALG depended on the influx of extracellular Ca2+via the SOCE Ca2+ permeable plasma membrane channels. ALG-CM also activated NK cell cytokine production of IFN-γ and TNF-α through a partly Ca2+-independent mechanism. This work highlights the non-equivalence between alginate dressings for NK cell stimulation and shows that the pure calcium alginate dressing Algosteril® enhances NK cell cytotoxic and immuno-modulatory activities. Altogether, these results underline a specific property of this medical device in innate defense that is key for the cutaneous wound healing process

AHR: leukemic countermeasure against NK cells

International audienceIn this issue of Blood, Scoville et al report an original mechanism by which the aryl hydrocarbon receptor (AHR) allows acute myeloid leukemia (AML) to escape the natural killer (NK) cell-mediated antitumor immunosurveillance by increasing expression of microRNA (miR)-29b, thereby inhibiting NK-cell maturation and function.

Editorial: Innate Anti-Tumor Immune Responses in Solid and Hematological Malignancies: From Basic Research to Clinical Applications

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Valpha24-JalphaQ-independent, CD1d-restricted recognition of alpha-galactosylceramide by human CD4(+) and CD8alphabeta(+) T lymphocytes

Human CD1d molecules present an unknown ligand, mimicked by the synthetic glycosphingolipid -galactosylceramide (GC), to a highly conserved NKT cell subset expressing an invariant TCR V24-JQ paired with V11 chain (V24+V11+ invariant NK T cell (NKTinv)). The developmental pathway of V24+V11+NKTinv is still unclear, but recent studies in mice were consistent with a TCR instructive, rather than a stochastic, model of differentiation. Using CD1d-GC-tetramers, we demonstrate that in humans, TCR variable domains other than V24 and V11 can mediate specific recognition of CD1d-GC. In contrast to V24+V11+NKTinv cells, V24-/CD1d-GC-specific T cells express either CD8 or CD4 molecules, but they are never CD4 CD8 double negative. We show that CD8+V24-/CD1d-GC-specific T cells exhibit CD8-dependent specific cytotoxicity and have lower affinity TCRs than V24+/CD1d-GC-specific T cells. In conclusion, our results demonstrate that, contrary to the currently held view, recognition of CD1d-GC complex in humans is not uniformly restricted to the V24-JQ/V11 NKT cell subset, but can be mediated by a diverse range of V and V domains. The existence of a diverse repertoire of CD1d-GC-specific T cells in humans strongly supports their Ag-driven selection. <br/

Lymphocytes NK : un rôle majeur dans le contrôle immunologique de la leucémie myéloïde chronique

Les dernières études menées sur la leucémie myéloïde chronique (LMC) ont permis de mettre en évidence le rôle clé des cellules NK (natural killer) dans cette maladie avec trois enseignements majeurs : (1) au diagnostic, les cellules NK sont anormales dans leurs propriétés phénotypiques et fonctionnelles ; (2) un traitement standard par inhibiteur de tyrosine kinase (ITK) est associé à la correction de certaines anomalies, en particulier celles des lymphocytes NK ; (3) le taux du sous-type mature NK CD56dim pourrait être un facteur du maintien d’une survie sans rechute après une stratégie d’arrêt de traitement par ITK. Ces données renforcent le rôle des lymphocytes NK dans le contrôle immunologique de la LMC