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IntroductionAnaplastic large-cell lymphomas (ALCLs) represent a subset of neoplasms with distinctive genetic defects that are immunophenotypically characterized by the sustained expression of CD30. 1 In the late 1980s several groups described the unique association of the t(2;5)(p23;q35) chromosome translocation with ALCL. However, the corresponding genes were discovered several years later by Morris and colleagues. 2 In the t(2;5)(p23;q35) translocation the ALK (anaplastic lymphoma kinase) gene on chromosome 2 is fused to the NPM1 (nucleophosmin) gene on chromosome 5. Recently, several groups have successfully cloned many additional ALK translocations. 3 Translocations of ALK have also been discovered in inflammatory myofibroblastic tumors (IMTs), 4 and deregulated expression of ALK has been documented in a subgroup of diffuse large-cell lymphomas (DLCL). [5][6][7] Notably, the constitutive expression of the wild-type ALK receptor (ALK-R) has been shown in several cancer cell lines 8 and in primary neuroblastoma and rhabdomyosarcoma. 9,10 The ALK gene encodes a tyrosine kinase receptor whose physiologic expression in mammals is largely limited to neuronal cells. 11,12 At present, the physiologic role of ALK is still largely unclear. Nevertheless, ALK and its ligand play an important role in the formation of visceral muscle in Drosophila, 13,14 and in the regulation of neurologic synapses in Caenorhabditis elegans. 15 All ALK fusion proteins maintain the intracytoplasmic moiety of the ALK-R at their C terminus. This region, which contains the catalytic domain, is required for cellular transformation, 16 whereas the N-terminal fusion partners act as dimerizing domains. 17,18 Activated ALK chimeras bind multiple adaptor proteins such as Grb2, Shc, IRS-1, and p130Cas, which link them to diverse pathways regulating cell proliferation, survival, and cell transformation. Among them, PLC-␥, PI3K, and Jak3 lead to the activation of numerous downstream molecules including cyclin D, Erk1/2, STAT3, and AKT. 19,20 Using cell lineage-specific conditional knock-out models, we have recently demonstrated that the genetic ablation of STAT3 in ALK ϩ cells leads to T-and B-cell death, and prevents the generation of B-cell neoplasms. 21 Previously, PLC-␥ and AKT have been shown to play an essential role in ALK-mediated transformation, in vitro. 16,[22][23][24] Thus, it is conceivable that the inhibition of ALK could induce biologic changes capable of inhibiting cell growth and/or promoting cell death. This hypothesis is supported by a study in which a nonselective, but active drug against ALK was shown to successfully lead to tumor cell death. 25 Nonetheless, the specific down-modulation of NPM-ALK mRNA via siRNA does not induce apoptosis, despite a significant reduction in NPM-ALK protein. 26 Thus, the formal demonstration that the specific loss of ALK kinase activity has relevant biologic effects is still missing. Several kinase inhibitors were recently developed and successfully used in the treatment of human tumors. Systematic ...

Interferon-gamma (IFN-gamma) is produced by activated T lymphocytes and plays a regulatory role in immune responses. The nature and location of cells that express the IFN-gamma receptor (R) and respond to this lymphokine are not well documented. The distribution of human IFN-gamma-R (HuIFN-gamma-R) was, therefore, investigated in situ by immunohistochemistry, using affinity-purified rabbit polyclonal antibodies directed against the extracellular domain of the receptor. In lymphoid organs, IFN-gamma-R expression is restricted to the B cell areas of lymph nodes, adult and fetal spleen, tonsils, appendix, and mucosa-associated lymphoid tissue of the small bowel. Macrophages and other reticular cells in lymphoid tissues and other organs are strongly positive for IFN-gamma-R, whereas its expression was consistently negative in the cortical and medullary thymocytes. Two-color flow cytofluorometric analysis of blood, lymph node, tonsil, spleen and thymus cells confirms that most B lymphocytes are IFN-gamma-R positive, whereas T lymphocytes are negative. However, after in vitro activation, peripheral blood T cells become IFN-gamma-R+. In non-lymphoid organs, IFN-gamma-R is expressed on endothelial cells of the medium- and small-size vessels. In epithelial tissues, high expression of IFN-gamma-R is detected on trophoblastic epithelium, glandular cells of stomach, ileum and colon, lung alveolar cells, salivary duct cells, renal tubular cells, and endometrial mucosa cells. Hepatocytes are weakly positive, while squamous epithelial cells are negative. The distribution of the HuIFN-gamma-R is discussed in view of the known functions of IFN-gamma.

Ag presentation by dendritic cells (DC) is essential to effective antitumor T cell responses in cancer patients. Depending on their origin, maturation state, and the ambient cytokine milieu, DC can differentiate into distinct subpopulations, which preferentially either induce Th1 cell activation (CD11c+,CD123− myeloid DC (MDC)) or immunosuppressive T cell development (CD11c−,CD123+ plasmacytoid DC (PDC)). The present study was undertaken to characterize the effects of pancreatic carcinoma cell-derived cytokines on immature monocyte-derived DC (iMo-DC) in vitro and in vivo. Medium conditioned by human pancreatic carcinoma cells inhibited iMo-DC proliferation, expression of costimulatory molecules (CD80 and CD40) and of HLA-DR, and functional activity as assessed by MLR and IL-12p70 production. iMo-DC generated from pancreatic carcinoma patients in advanced stages of the disease similarly showed decreased levels of HLA-DR expression and reduced ability to stimulate MLR in response to CD40L and IFN-γ. Moreover, in tumor-patient peripheral blood, the ratio of MDC to PDC cells was lower than in healthy controls due to reduced numbers of MDC CD11c+ cells. Importantly, rather than a single cytokine, a combination of tumor-derived cytokines was responsible for these effects; these were primarily TGF-β, IL-10, and IL-6, but not vascular endothelial growth factor. In summary, we have identified an array of pancreatic carcinoma-derived cytokines that cooperatively affect iMo-DC activation in a manner consistent with ineffective antitumor immune responses.