Pharmacological activation of the STING (stimulator of interferon genes)–controlled innate immune pathway is a promising therapeutic strategy for cancer. Here we report the identification of MSA-2, an orally available non-nucleotide human STING agonist. In syngeneic mouse tumor models, subcutaneous and oral MSA-2 regimens were well tolerated and stimulated interferon-β secretion in tumors, induced tumor regression with durable antitumor immunity, and synergized with anti–PD-1 therapy. Experimental and theoretical analyses showed that MSA-2 exists as interconverting monomers and dimers in solution, but only dimers bind and activate STING. This model was validated by using synthetic covalent MSA-2 dimers, which were potent agonists. Cellular potency of MSA-2 increased upon extracellular acidification, which mimics the tumor microenvironment. These properties appear to underpin the favorable activity and tolerability profiles of effective systemic administration of MSA-2.

Hepatocellular carcinoma (HCC) is a highly malignant tumor, and chronic infection with hepatitis B virus is one of its major risk factors. To identify the proteins involved in HCC carcinogenesis, we used two-dimensional fluorescence DIGE to study the differentially expressed proteins in tumor and adjacent nontumor tissue samples. Samples from 12 hepatitis B virus-associated HCC patients were analyzed. A total of 61 spots were significantly up-regulated (ratio > 2, p < 0.01) in tumor samples, whereas 158 spots were down-regulated (ratio < ؊2, p < 0.01). Seventyone gene products were identified among these spots. Members of the heat shock protein 70 and 90 families were simultaneously up-regulated, whereas metabolismassociated proteins were decreased in HCC samples. The down-regulation of mitochondrial and peroxisomal proteins in these results suggested loss of special organelle functions during HCC carcinogenesis. Four metabolic enzymes involved in the methylation cycle in the liver were down-regulated in HCC tissues, indicating S-adenosylmethionine deficiency in HCC. Two gene products, glyceraldehyde-3-phosphate dehydrogenase and formimidoyltransferase-cyclodeaminase, were identified from inversely altered spots, suggesting that different isoforms or post-translational modifications of these two proteins might play different roles in HCC. For the first time, the overexpression of Hcp70/Hsp90-organizing protein and heterogeneous nuclear ribonucleoproteins C1/C2 in HCC tissues was confirmed by Western blot and then by immunohistochemistry staining in 70 HCC samples, suggesting their potential as protein tumor markers. In summary, we profiled proteome alterations in HCC tissues, and these results may provide useful insights for understanding the mechanism involved in the process of Proteomics analysis is currently considered to be a powerful tool for global evaluation of protein expression, and proteomics has been widely applied in analysis of diseases, especially in fields of cancer research. Quantitative protein expression profiling is a crucial part of proteomics, and such profiling requires methods that are able to efficiently provide accurate and reproducible differential expression values for proteins in two or more biological samples. Two-dimensional electrophoresis (2DE) 1 was a technique that was widely used for proteomics research. However, intergel variation and excessive time/labor costs have been common problems with standard 2DE. Two-dimensional (2D) DIGE might therefore be considered as one of the most significant advances in quantitative proteomics. Using the 2D DIGE approach, different samples prelabeled with mass-and charge-matched fluorescent cyanine dyes are co-separated in the same 2D gel, and an internal standard is used in every gel that has negated the problem of intergel variation (1). Moreover with the great sensitivity and dynamic range that is afforded by these dyes, 2D DIGE can give greater accuracy of quantitation than silver staining (2). It has been reported that the correlation betw...

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Naïve T cells, when activated by specific antigen and cytokines, up-regulate adhesion molecules as well as chemokine receptors on their surface, which allows them to migrate to inflamed tissues. Human studies have shown that CXCR3 is one of the chemokine receptors that is induced during T cell activation. Moreover, CXCR3-positive T cells are enriched at inflammatory sites in patients with autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. In this study, we use a mouse model of inflammation to demonstrate that CXCR3 is required for activated T cell transmigration to inflamed tissue. Using an anti- mCXCR3 antibody, we have shown that in vitro-differentiated T helper (Th) 1 and Th2 cells up-regulated CXCR3 upon stimulation with specific antigen/major histocompatibility complex. However, only Th1 cells, when adoptively transferred to syngeneic recipients, are efficiently recruited to the peritoneum in an adjuvant-induced peritonitis model. Furthermore, the neutralizing anti-mCXCR3 antibody profoundly inhibits the recruitment of Th1 cells to the inflamed peritoneum. Real-time, quantitative reverse transcriptase-polymerase chain reaction analysis demonstrates that the CXCR3 ligands, interferon (IFN)-inducible protein 10 (CXCL10) and IFN-inducible T cell alpha chemoattractant (CXCL11), are among the many chemokines induced in the adjuvant-treated peritoneum. The anti-mCXCR3 antibody is also effective in inhibiting a delayed-type hypersensitivity response, which is largely mediated by enhanced trafficking of activated T cells to peripheral inflammatory sites. Collectively, our results suggest that CXCR3 has a critical role in T cell transmigration to sites of inflammation and thus, may serve as a molecular target for anti-inflammatory therapies.

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