Therapeutic antibodies that target T-cell co-inhibitory molecules display potent antitumor effects in multiple types of cancer. LSECtin is a cell surface lectin of the DC-SIGN family expressed in dendritic cells that inhibits T-cell responses. LSECtin limits T-cell activity in infectious disease, but it has not been studied in cancer. Here we report the finding that LSECtin is expressed commonly in melanomas where it blunts tumor-specific T-cell responses. When expressed in B16 melanoma cells, LSECtin promoted tumor growth, whereas its blockade slowed tumor growth in either wild-type or LSECtin-deficient mice. The tumor-promoting effects of LSECtin were abrogated in Rag1 À/À mice or in response to CD4 þ or CD8 þ T-cell depletion. Mechanistic investigations determined that LSECtin inhibited the proliferation of tumor-specific effector T cells by downregulating the cell cycle kinases CDK2, CDK4, and CDK6. Accordingly, as expressed in B16, tumor cells LSECtin inhibited tumorspecific T-cell responses relying upon proliferation in vitro and in vivo. Notably, LSECtin interacted with the coregulatory molecule LAG-3, the blockade of which restored IFNg secretion that was reduced by melanomaderived expression of LSECtin. Together, our findings reveal that common expression of LSECtin in melanoma cells engenders a mechanism of immune escape, with implications for novel immunotherapeutic combination strategies. Cancer Res; 74(13); 3418-28. Ó2014 AACR.

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Our results reveal that LSECtin is a novel regulator of T cells and expose a crucial mechanism for hepatic T-cell immune suppression, perhaps opening up a new approach for treatment of inflammatory diseases in the liver.

BackgroundOphiocordyceps sinensis, a worm and fungus combined mixture which Hirsutella sinensis is parasitic on the caterpillar body, has been used as a traditional medicine or healthy food in China for thousands of years. H. sinensis is reported as the only correct anamorph of O. sinensis and its main active ingredients are similar to the natural O. sinensis.ResultsH. sinensis L0106, asexual strain of O. sinensis, was isolated and identified in this study. Three transcriptomes of H. sinensis at different cultivation periods (growth period 3d, pre-stable period 6d and stable period 9d) were sequenced for the first time by RNA-Seq method, and 25,511 unigenes (3d), 25,214 unigenes (6d) and 16,245 unigenes (9d) were assembled and obtained, respectively. These unigenes of the three samples were further assembled into 20,822 unigenes (All), and 62.3 percent of unigenes (All) could be annotated based on protein databases. Subsequently, the genes and enzymes involved in the biosynthesis of the active ingredients according to the sequencing and annotation results were predicted. Based on the predictions, we further investigated the interaction of different pathway networks and the corresponding enzymes. Furthermore, the differentially expressed genes (DEGs) of H. sinensis grown during different developmental stages (3d-VS-6d, 3d-VS-9d and 6d-VS-9d) were globally detected and analyzed based on the data from RNA-Seq, and 764 DEGs between 3d and 6d, 1,869 DEGs between 3d and 9d, and 770 DEGs between 6d and 9d were found, respectively.ConclusionsThis work presented here would aid in understanding and carrying out future studies on the genetic basis of H. sinensis and contribute to the further artificial production and application of this organism. This study provided a substantial contribution and basis to further characterize the gene expression profiles of H. sinensis in the metabolic pathways of active ingredients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1269-y) contains supplementary material, which is available to authorized users.

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