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Myeloid dendritic cells (mDCs) recognize and respond to polyI:C, an analog of dsRNA, by endosomal Toll-like receptor (TLR) 3 and cytoplasmic receptors. Natural killer (NK) cells are activated in vivo by the administration of polyI:C to mice and in vivo are reciprocally activated by mDCs, although the molecular mechanisms are as yet undetermined. Here, we show that the TLR adaptor TICAM-1 (TRIF) participates in mDC-derived antitumor NK activation. In a syngeneic mouse tumor implant model (C57BL/6 vs. B16 melanoma with low H-2 expresser), i.p. administration of polyI:C led to the retardation of tumor growth, an effect relied on by NK activation. This NK-dependent tumor regression did not occur in TICAM-1⁻/⁻ or IFNAR⁻/⁻ mice, whereas a normal NK antitumor response was induced in PKR⁻/⁻, MyD88⁻/⁻, IFN-β⁻/⁻, and wild-type mice. IFNAR was a prerequisite for the induction of IFN-α/β and TLR3. The lack of TICAM-1 did not affect IFN production but resulted in unresponsiveness to IL-12 production, mDC maturation, and polyI:C-mediated NK-antitumor activity. This NK activation required NK-mDC contact but not IL-12 function in in vivo transwell analysis. Implanted tumor growth in IFNAR⁻/⁻ mice was retarded by adoptively transferring polyI:C-treated TICACM-1-positive mDCs but not TICAM-1⁻/⁻ mDCs. Thus, TICAM-1 in mDCs critically facilitated mDC-NK contact and activation of antitumor NK, resulting in the regression of low MHC-expressing tumors.

Minor histocompatibility antigens (mHag) were originally identified as antigens causing graft rejection or graft‐versus‐host disease in human leukocyte antigen (HLA)‐matched allogeneic transplantation. Molecular identification has revealed most to be major histocompatibility complex (MHC)‐bound short peptide fragments encoded by genes which are polymorphic due to single nucleotide polymorphisms (SNP). Genotypic disparity of SNP between transplantation donors and recipients gives rise to mHag as non‐self antigens for both the donor and the recipient. Subsequently, mHag have been explored as immunotherapeutic antigens for use against recurring hematological malignancies after allogeneic hematopoietic cell transplantation (HCT), because mHag expressed only on hematopoietic cells are considered to augment graft‐versus‐leukemia/lymphoma (GVL) effects without increasing the risk of life‐threatening graft‐versus‐host disease (GVHD). Accumulating evidence suggests that T‐cell responses to mHag aberrantly expressed on solid tumor cells are also involved in the eradication of sensitive tumors such as renal cell carcinomas following HCT. Over the past decade, the number of putative GVL‐directed mHag has increased to a level that covers more than 30% of the Japanese patient population, so that clinical trials may now be executed in the setting of either vaccination or adoptive immunotherapy. As it is expected that immune responses to alloantigens are more powerful than to tumor antigens mostly derived from overexpressed self‐proteins, mHag‐based immunotherapy may lead to a new treatment modality for high‐risk malignancies following allogeneic HCT. (Cancer Sci 2007; 98: 1139–1146)

The efficient isolation and ex vivo expansion of antigen-specific T cells are crucial for successful adoptive immunotherapy against uncontrollable infections and cancers. Several methods have been reported for this purpose, for example, employing MHC-multimeric complexes, interferon-gamma secretion, and antibodies specific for molecules expressed on T-cell surfaces, including CD25, CD69, CD107a, CD137, and CD154. Of the latter, CD137 has been shown to be one of the most promising targets since it is only expressed on CD8 + T cells early after encountering antigen, while being almost undetectable on resting cells. However, detailed comparisons between CD137-based and other methods have not yet been conducted. In this study, we therefore compared three approaches (with CD137, CD107a, and tetramers) using HLA-A24-restricted CMV pp65 and EBV BRLF1 epitopes as model antigens. We found that the CD137-based isolation of antigen-stimulated CD8 + T cells was comparable to tetramer-based sorting in terms of purity and superior to the other two methods in terms of subsequent cell expansion. The method was less applicable to CD4 + T cells since their CD137 upregulation is not sufficiently high. Collectively, this approach is most likely to be optimal among the methods tested for the isolation and expansion of antigen-specific CD8 + cells.

Individualized outcome prediction classifiers were successfully constructed through expression profiling of a total of 8644 genes in 50 non-small-cell lung cancer (NSCLC) cases, which had been consecutively operated on within a defined short period of time and followed up for more than 5 years. The resultant classifier of NSCLCs yielded 82% accuracy for forecasting survival or death 5 years after surgery of a given patient. In addition, since two major histologic classes may differ in terms of outcome-related expression signatures, histologic-type-specific outcome classifiers were also constructed. The resultant highly predictive classifiers, designed specifically for nonsquamous cell carcinomas, showed a prediction accuracy of more than 90% independent of disease stage. In addition to the presence of heterogeneities in adenocarcinomas, our unsupervised hierarchical clustering analysis revealed for the first time the existence of clinicopathologically relevant subclasses of squamous cell carcinomas with marked differences in their invasive growth and prognosis. This finding clearly suggests that NSCLCs comprise distinct subclasses with considerable heterogeneities even within one histologic type. Overall, these findings should advance not only our understanding of the biology of lung cancer but also our ability to individualize postoperative therapies based on the predicted outcome.

Epstein–Barr virus (EBV) nuclear antigen (EBNA)1 is expressed in every EBV‐infected cell, regardless of the state of EBV infection. Although EBNA1 is thought to be a promising antigen for immunotherapy of all EBV‐associated malignancies, it is less clear whether EBNA1‐specific CD4+ T cells can act as direct effectors. Herein, we investigated the ability of CD4+ T‐cell clones induced with overlapping peptides covering the C‐terminal region of EBNA1, and identified minimal epitopes and their restricted major histocompatibility complex class II molecules. Of these, a novel epitope, EYHQEGGPD, was found to be presented by DRB1*0401, 0403 and 0406. Five CD4+ T‐cell clones recognized endogenously processed and presented antigens on EBV‐transformed lymphoblastoid cell lines (LCL) and one example proved capable of killing EBV‐carrying natural killer (NK) and T‐cell lines derived from patients with chronic active EBV infection (CAEBV). Identification of minimal epitopes facilitates design of peptide‐based vaccines and our data suggest that EBNA1‐specific CD4+ T cells may play roles as direct effectors for immunotherapy targeting EBV‐carrying NK and T‐cell malignancies. (Cancer Sci 2008; 99: 1633–1642)

Mice lacking the RelA (p65) subunit of NF-κ B die between days 14 and 15 of embryogenesis because of massive liver destruction. Fibroblasts and macrophages isolated from relA-/- embryos were found to be highly sensitive to tumor necrosis factor (TNF) cytotoxicity, raising the possibility that endogenous TNF is the cause of liver cell apoptosis. To test this idea, we generated mice lacking both TNF and RelA. Embryogenesis proceeds normally in such mice, and TNF/RelA double-deficient mice are viable and have normal livers. Thus, the RelA-mediated antiapoptotic signal that protects normal cells from TNF injury in vitro can be shown to be operative in vivo.

This report concerns the clinicopathologic features of 4 patients with CD56/neural cell adhesion molecule (NCAM)-positive Langerhans cell sarcoma (LCS). Three of the patients were elderly, between 59 and 62 years of age at presentation, and the other was 35 years old. The presenting symptoms included fever, bone pain, and weakness. The patients shared some clinical findings, such as multiorgan involvement of lymph nodes, skin, lung, bone marrow, and spleen. LCS carries a poor prognosis, and 3 of the patients died of the disease within several years of presentation despite multiagent chemotherapy and radiotherapy. Of special interest is that all of the cases showed CD56 expression on the tumor cells in addition to expression of CD1a, S100beta, and langerin, the presence of which suggests derivation from Langerhans cells. For control, CD56 was also examined in 8 cases of Langerhans cell histiocytosis (LCH), a single-system unifocal or multifocal disease, and the results of staining of the tumor cells were negative. Our findings indicated that CD56 may be a clinically relevant biologic marker for predicting an intractable course of Langerhans cell neoplasms, although it is often difficult to draw a definite morphologically-based distinction between LCS and LCH.

Partial human leukocyte antigen (HLA)‐mismatched hematopoietic stem cell transplantation (HSCT) is often performed when an HLA‐matched donor is not available. In these cases, CD8+ or CD4+ T cell responses are induced depending on the mismatched HLA class I or II allele(s). Herein, we report on an HLA‐DRB1*08:03‐restricted CD8+ CTL clone, named CTL‐1H8, isolated from a patient following an HLA‐DR‐mismatched HSCT from his brother. Lysis of a patient Epstein–Barr virus‐transformed B cell line (B‐LCL) by CTL‐1H8 was inhibited after the addition of blocking antibodies against HLA‐DR and CD8, whereas antibodies against pan‐HLA class I or CD4 had no effect. The 1H8‐CTL clone did not lyse the recipient dermal fibroblasts whose HLA‐DRB1*08:03 expression was upregulated after 1 week cytokine treatment. Engraftment of HLA‐DRB1*08:03‐positive primary leukemic stem cells in non‐obese diabetic/severe combined immunodeficient/γc‐null (NOG) mice was completely inhibited by the in vitro preincubation of cells with CTL‐1H8, suggesting that HLA‐DRB1*08:03 is expressed on leukemic stem cells. Finally, analysis of the precursor frequency of CD8+ CTL specific for recipient antigens in post‐HSCT peripheral blood T cells revealed a significant fraction of the total donor CTL responses towards the individual mismatched HLA‐DR antigen in two patients. These findings underscore unexpectedly significant CD8 T cell responses in the context of HLA class II. (Cancer Sci 2011; 102: 1281–1286)

It has been shown that allogeneic hematopoietic stem cell transplantation (HSCT) can be one of the therapeutic options for patients with metastatic solid tumors, such as renal cancer. However, the development of relatively severe GVHD seems to be necessary to achieve tumor regression in the current setting. Thus, it is crucial to identify minor histocompatibility antigens (mHags) only expressed in tumor cells but not GVHD target organs. In this study, we examined whether three mHags: ACC-1 and ACC-2 encoded by BCL2A1 , and HA-1 encoded by HMHA1 , could serve as such targets for melanoma. Real-time PCR and immunohistochemical analysis revealed that the expression of both BCL2A1 and HMHA1 in melanoma cell lines and primary melanoma cells was comparable to that of hematopoietic cells. Indeed, melanoma cell lines were efficiently lysed by cytotoxic T lymphocytes specific for ACC-1, ACC-2, and HA-1. Our data suggest that targeting mHags encoded not only by HMHA1 , whose aberrant expression in solid tumors has been reported, but also BCL2A1 may bring about beneficial selective graft-versus-tumor effects in a population of melanoma patients for whom these mHags are applicable.

Smad family members are essential intracellular signaling components of the transforming growth factor-beta (TGF-beta) superfamily involved in a range of biological activities. Two highly homologous molecules, Smad2 and Smad3, have so far been identified as receptor-activated Smads for TGF-beta signaling and have become the focus of intensive studies. However, no definite differences in regulation or function have been established between these TGF-beta signaling molecules. In the present study, we show that the expression of Smad3, but not its close relative, Smad2, is down-regulated by TGF-beta mediated signals themselves in human lung epithelial cells. This down-regulation of Smad3 by TGF-beta treatment did not appear to result from shortening of the half-life of Smad3 mRNA. Constitutive expression of Smad3 in the presence of TGF-beta induced apoptotic cell death, with an adverse effect on the cell growth of human lung epithelial cells. Apoptotic cell death could also be induced by forced expression of Smad2 in the presence of TGF-beta, but less efficiently than by that of Smad3. These findings clearly define the distinctions between Smad2 and Smad3 for the first time in that a qualitative difference was observed with regard to the regulation of their expression in response to TGF-beta, while Smad2 and Smad3 appeared to have quantitatively different capabilities regarding the induction of apoptotic cell death in human lung epithelial cells.