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NK cells play an important role in tumor immunosurveillance and largely contribute to the therapeutic success of anti-tumor antibodies like Rituximab. Here, we studied the role of the TNF family member 4-1BB ligand (4-1BBL) during the interaction of NK cells with chronic lymphocytic leukemia (CLL) cells. 4-1BBL was highly expressed on patient B-CLL cells in all 56 investigated cases. Signaling via 4-1BBL following interaction with 4-1BB, which was detected on NK cells of CLL patients but not healthy individuals, led to the release of immunoregulatory cytokines including TNF by CLL cells. CLL patient sera contained elevated levels of TNF and induced 4-1BB upregulation on NK cells, which in turn impaired direct and Rituximab-induced NK-cell reactivity against 4-1BBL-expressing targets. NK-cell reactivity was not only enhanced by blocking the interaction of NK cell-expressed 4-1BB with 4-1BBL expressed by CLL cells, but also by preventing 4-1BB upregulation on NK cells via neutralization of TNF in patient serum with Infliximab. Our data indicate that 4-1BBL mediates NK-cell immunosubversion in CLL, and thus might contribute to the reportedly compromised efficacy of Rituximab to induce NK-cell reactivity in the disease, and that TNF neutralization may serve to enhance the efficacy of Rituximab treatment in CLL.
NK cells play an important role in tumor immunosurveillance and largely contribute to the therapeutic success of anti-tumor antibodies like Rituximab. Here, we studied the role of the TNF family member 4-1BB ligand (4-1BBL) during the interaction of NK cells with chronic lymphocytic leukemia (CLL) cells. 4-1BBL was highly expressed on patient B-CLL cells in all 56 investigated cases. Signaling via 4-1BBL following interaction with 4-1BB, which was detected on NK cells of CLL patients but not healthy individuals, led to the release of immunoregulatory cytokines including TNF by CLL cells. CLL patient sera contained elevated levels of TNF and induced 4-1BB upregulation on NK cells, which in turn impaired direct and Rituximab-induced NK-cell reactivity against 4-1BBL-expressing targets. NK-cell reactivity was not only enhanced by blocking the interaction of NK cell-expressed 4-1BB with 4-1BBL expressed by CLL cells, but also by preventing 4-1BB upregulation on NK cells via neutralization of TNF in patient serum with Infliximab. Our data indicate that 4-1BBL mediates NK-cell immunosubversion in CLL, and thus might contribute to the reportedly compromised efficacy of Rituximab to induce NK-cell reactivity in the disease, and that TNF neutralization may serve to enhance the efficacy of Rituximab treatment in CLL.
Acute myeloid leukemia (AML) cells are killed by allogeneic NK cells. However, autologous NK cells from AML patients express decreased levels of activating receptors, and show reduced cytotoxicity. Here, we investigated how interactions between NK and AML cells might cause loss of NK-cell activity in patients. Our results show that AML cell lines and primary blasts alter the NK-cell phenotype, reducing their cytotoxic potential upon prolonged contact. Downregulation of NK-cell-activating receptors was contactdependent and correlated with conjugate formation. Time-lapse imaging of HL60 AML cell line and NK-cell interactions showed a high proportion of noncytolytic contacts. Studies of NK-cell immunological synapses revealed a defect in lytic synapse formation. Namely, despite correct F-actin and LFA-1 recruitment, polarization of lytic granules toward primary blasts or AML cell lines was reduced. The NK-AML cell line synapses showed impairment of CD3ζ recruitment. Attempts to correct these synapse defects by cytokine stimulation of NK cells improved conjugate formation, but not granule polarization. Pretreatment of AML cell lines with the immunomodulating molecule lenalidomide significantly enhanced granule polarization. We speculate that combining immunomodulatory drugs and cytokines could increase AML cell sensitivity to autologous NK cells and reinforce the activity of allogeneic NK cells in adoptive immunotherapy.Keywords: Acute myeloid leukemia r Cancer immunity r Cytotoxicity r Immunological synapse r NK-cell-activating receptors Additional supporting information may be found in the online version of this article at the publisher's web-site [6,7]. AML cells express ligands interacting with NK-cell-activating receptors, making them susceptible to killing by NK cells [8,9]. However, autologous NK cells do not effectively control AML growth in patients. Some mechanisms have been suggested for AML escape, including downregulation of the ligands for NK-cellactivating receptors, secretion of soluble forms of these ligands, or upregulation of ligands for NK-cell inhibitory receptors [10]. Reduced toxicity has also been linked to downregulation of activating receptors on NK cells, particularly NKG2D and the natural cytotoxicity receptors (NCRs) NKp46 and NKp30 [11][12][13]. Upon remission, the NK-cell phenotype and function normalize, suggesting that the presence of AML blasts is responsible for the defects observed [12]. Interestingly, once out of the AML environment, NK cells that had previously expressed low levels of activating receptors regain their activity, becoming cytotoxic toward autologous leukemic blasts in mice [13]. This further implicates contact with AML cells in NK-cell activity down-modulation.Interaction between NK cells and a cancerous cell involves a series of steps resulting in the formation of an immunological synapse (NKIS) [14]. Upon first contact, the NK-cell cytoskeleton is reorganized in the zone of contact with the target cell (TC) [15]. Lytic granules are then polarized and their cont...
Since the postulation of the “missing‐self” concept, much progress has been made in defining requirements for NK‐cell activation. Unlike T lymphocytes that process signals from receptors in a hierarchic manner dominated by the T‐cell receptors, NK cells integrate receptor signals more “democratically.” Signals originate not only the downstream of cell‐surface receptors triggered by membrane‐bound ligands or cytokines, but are also mediated by specialized microenvironmental sensors that perceive the cellular surrounding by detecting metabolites or the availability of oxygen. Thus, NK‐cell effector functions are driven in an organ and disease‐dependent manner. Here, we review the latest findings on how NK‐cell reactivity in cancer is determined by the reception and integration of complex signals. Finally, we discuss how this knowledge can be exploited to guide novel combinatorial approaches for NK‐cell‐based anticancer therapies.
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