Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumours in nude mice. The EML4-ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC.

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In the present first investigation of EML4-ALK fusion in a large study of lung cancers (5/221), we found an interesting histotype-genotype relationship. Furthermore, we could detect the fusion protein by immunohistochemistry, pointing to possible clinical applications.

NK-cell function is regulated by the integration of signals received from activating and inhibitory receptors. Here we show that a novel immune receptor, T-cell Ig and mucin-containing domain-3 (Tim-3), is expressed on resting human NK cells and is up-regulated on activation. The NK92 NK-cell line engineered to overexpress Tim-3 showed a marked increase in IFN-␥ production in the presence of soluble rhGal-9 or Raji tumor cells engineered to express Gal-9. The Tim-3 ؉ population of low-dose IL-12/IL-18-activated primary NK cells significantly increased IFN-␥ production in response to soluble rhGal-9, Gal-9 presented by cell lines, and primary acute myelogenous leukemia (AML) targets that endogenously express Gal-9. This effect is highly specific as Tim-3 Ab blockade significantly decreased IFN-␥ production, and Tim-3 cross-linking induced ERK activation and degradation of IB␣. Exposure to Gal-9-expressing target cells had little effect on CD107a degranulation. Reconstituted NK cells obtained from patients after hematopoietic cell transplantation had diminished expression of Tim-3 compared with paired donors. This observation correlates with the known IFN-␥ defect seen early posttransplantation. In conclusion, we show that Tim-3 functions as a human NK-cell coreceptor to enhance IFN-␥ production, which has important implications for control of infectious disease and cancer. (Blood. 2012;119(13): 3064-3072) IntroductionHuman NK cells are lymphocytes that develop from hematopoietic progenitor cells in the BM and secondary lymphoid tissues. 1 Peripheral blood (PB) NK cells are phenotypically defined as expressing the surface receptor CD56 (neural cell adhesion molecule [NCAM]) and lacking expression of CD3. 2 They mediate their function through the exocytosis of lytic granules that contain perforin and granzymes, 3 the expression of death receptor ligands, 4 the expression of FcR␥III, which mediates Ab-dependent cellmediated cytotoxicity, 5 and the secretion of cytokines and chemokines. 6 As a result, NK cells take part in both the innate and adaptive immune systems and play important roles in the control of viral infections, pregnancy, tumor immunosurveillance, and hematopoietic cell transplantation (HCT). 7,8 The ability of NK cells to differentiate normal healthy cells (self) from virally infected or malignantly transformed cells (nonself) is regulated by a sophisticated repertoire of cell-surface receptors that control their activation, proliferation, and effector functions. [9][10][11] Recently, a novel receptor, T-cell Ig and mucincontaining domain-3 (Tim-3), has been described to have various roles in immune regulation and is highly expressed on NK cells in mice and humans. [12][13][14][15][16][17] Tim-3 is a type I membrane glycoprotein that was first identified as a cell marker of terminally differentiated CD4 ϩ Th1 cells. 18 Galectin-9 (Gal-9), a 40-kDa S-type ␤-galactoside binding lectin, is a known ligand for Tim-3 and is highly expressed in tissues of the immune system, such as the BM, lymph nodes, thymu...

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC)is the third most frequent virus-associated human malignancy. How this tumor escapes immune recognition despite the expression of several viral antigens has remained poorly understood. Our previous in vitro studies have shown that NPC cells release exosomes containing high amounts of galectin-9, a ligand of the membrane receptor Tim-3, which is able to induce apoptosis in mature Th1 lymphocytes.Here, we sought to determine whether galectin-9-carrying exosomes were produced in NPC patients and whether such exosomes might play a role in the immune evasion of NPC cells. We report that galectin-9-containing exosomes are selectively detected in plasma samples from NPC patients and mice xenografted with NPC tumors. The incorporation into exosomes protects galectin-9 against proteolytic cleavage but retains its Tim-3-binding capacity. Importantly, NPC exosomes induce massive apoptosis in EBVspecific CD4 ؉ cells used as a model of target T cells. This effect is inhibited by both anti-Tim-3 and antigalectin-9 blocking antibodies. These results indicate that blocking galectin-9/Tim-3 interaction in vivo might alleviate the Th1-suppressive effect of NPC exosomes and sustain antitumoral T-cell responses and thereby improve clinical efficacy of immunotherapeutic approaches against NPC. (Blood. 2009;113:1957-1966 IntroductionNasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignancy and the third most frequent virus-associated human malignancy after hepatocarcinomas and cervix carcinomas. Each year, approximately 80 000 new cases are diagnosed worldwide. The geographic distribution of NPC is not uniform. It is relatively rare in European and North American countries. Very high incidence foci are found in South China, especially in Guandong and Guangxi provinces (25-40 per 100 000 per year). 1 Areas of intermediate incidence (approximately 3-8 per 100 000 per year) include a large number of developing or emerging countries, especially in North and Central Africa (Tunisia, Algeria, Morocco, Somalia, and Kenya) and in Southeast Asia (Philippines, Vietnam, Indonesia).NPC is an epithelial malignancy with a complex etiology involving viral, environmental, and hereditary factors. Except for some very rare cases of atypical highly differentiated NPC occurring in Western countries, the intact EBV genome is always contained in the nuclei of all malignant cells. 2,3 Many of the approximately 80 EBV genes are silent, but several viral RNAs and proteins are consistently expressed in NPC and contribute to the malignant phenotype. 4 NPC oncogenesis also requires a variable assortment of cellular genetic or epigenetic alterations. 5 Another important biologic feature of NPC is the presence of a massive lymphoid infiltrate in the primary tumor. This infiltrate contains mostly T lymphocytes and a minority of B cells, monocytes, dendritic cells, and eosinophils. The abundant production by malignant NPC cells of inflammatory cytokines, including interle...