Natural killer (NK) cells were discovered 40 years ago, by their ability to recognize and kill tumor cells without the requirement of prior antigen exposure. Since then, NK cells have been seen as promising agents for cell-based cancer therapies. However, NK cells represent only a minor fraction of the human lymphocyte population. Their skewed phenotype and impaired functionality during cancer progression necessitates the development of clinical protocols to activate and expand to high numbers ex vivo to be able to infuse sufficient numbers of functional NK cells to the cancer patients. Initial NK cell-based clinical trials suggested that NK cell-infusion is safe and feasible with almost no NK cell-related toxicity, including graft-versus-host disease. Complete remission and increased disease-free survival is shown in a small number of patients with hematological malignances. Furthermore, successful adoptive NK cell-based therapies from haploidentical donors have been demonstrated. Disappointingly, only limited anti-tumor effects have been demonstrated following NK cell infusion in patients with solid tumors. While NK cells have great potential in targeting tumor cells, the efficiency of NK cell functions in the tumor microenvironment is yet unclear. The failure of immune surveillance may in part be due to sustained immunological pressure on tumor cells resulting in the development of tumor escape variants that are invisible to the immune system. Alternatively, this could be due to the complex network of immune-suppressive compartments in the tumor microenvironment, including myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Although the negative effect of the tumor microenvironment on NK cells can be transiently reverted by ex vivo expansion and long-term activation, the aforementioned NK cell/tumor microenvironment interactions upon reinfusion are not fully elucidated. Within this context, genetic modification of NK cells may provide new possibilities for developing effective cancer immunotherapies by improving NK cell responses and making them less susceptible to the tumor microenvironment. Within this review, we will discuss clinical trials using NK cells with a specific reflection on novel potential strategies, such as genetic modification of NK cells and complementary therapies aimed at improving the clinical outcome of NK cell-based immune therapies.

A cell biology study using conditional gene knockout mouse models reveals a novel mechanism by which the actin cytoskeleton negatively regulates the signal transduction of the B cell antigen receptor.

Wiskott Aldrich syndrome (WAS) is caused by mutations in the WAS IntroductionWiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency caused by mutations of the WAS gene that is widely expressed within hematopoietic cells. 1 The clinical phenotype of WAS is characterized by congenital thrombocytopenia, combined immunodeficiency, and eczema. 1 The WAS protein (WASp) includes several functional domains that couple signal transduction to reorganization of the actin cytoskeleton. As a result, WASp has significant influence on processes such as cell adhesion, migration, assembly/turnover of cell surface receptors, and immunologic synapse formation. 1,2 Several studies in patients with WAS and in Was knock-out (WKO) mice have shown that WASp plays a critical role in the function of T and natural killer lymphocytes and dendritic cells. 1,3 However, the importance of WASp in B-cell development and function is less clearly defined. In vitro studies have shown that WASp-deficient B cells display defective actin polymerization on activation, 4 and impaired migration in response to CXCL13 5 ; however, calcium mobilization and proliferation after B-cell receptor ligation were found to be normal or only slightly reduced. 3 Studies in heterozygous Was ϩ/Ϫ mice have found progressive in vivo selection for WASp-expressing cells in T, B, and natural killer lineages. 6 Within the B-cell lineage, such selective advantage was especially prominent in marginal zone (MZ) B cells. 2,6 However, the in vivo effect of selective deficiency of WASp expression within a single lineage has not been analyzed so far and is of critical importance to understand WAS pathophysiology. Recently, with the use of a chimeric BM transplantation reconstitution model, Becker-Herman et al have provided evidence that lack of WASp expression in B lymphocytes causes immune dysregulation and may lead to fatal autoimmunity. 7 However, mixed chimerism in non-B lineages, irradiation-induced load of The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. 2819BLOOD, 22 MARCH 2012 ⅐ VOLUME 119, NUMBER 12For personal use only. on May 9, 2018. by guest www.bloodjournal.org From apoptotic bodies, and homeostatic B-cell proliferation may also have contributed to autoimmunity in that model.We describe here the generation of mice in which the Was locus has been floxed by homologous recombination. By crossing these mice to mb1-Cre knock-in mice, 8 which express the Cre recombinase under control of the CD79a promoter, the Was locus is selectively and efficiently deleted in B cells only, allowing analysis of the effect of B cell-restricted deficiency of WASp in vivo. Methods MiceAll mice were bred on a C57BL/6 background. WKO mice have been described. 3 Mb1-Cre mice 8 were a generous gift from Dr Michael Reth (Max Planck Institute of Immunobiology, ...

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