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One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine that potentiate T cell-mediated cytotoxicity, we identified atractylenolide I (ATT-I), which substantially promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of [CD8.sup.+] T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non-ATPase 4 (PSMD4), an essential component of the immunoproteasome complex, as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigen-processing activity of immunoproteasome, leading to enhanced MHC-I-mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient-derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of [CD8.sup.+] T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation and empowers T cell cytotoxicity, thus elevating the tumor response to immunotherapy., Introduction Current cancer immunotherapy is based on the longstanding immune surveillance hypotheses originating from the beginning of the 20th century. Regardless of diverse forms of cancer immunotherapy, they all share [...]

Immune evasion is a pivotal event in tumor progression. To eliminate human cancer cells, current immune checkpoint therapy is set to boost [CD8.sup.+] T cell-mediated cytotoxicity. However, this action is eventually dependent on the efficient recognition of tumor-specific antigens via T cell receptors. One primary mechanism by which tumor cells evade immune surveillance is to downregulate their antigen presentation. Little progress has been made toward harnessing potential therapeutic targets for enhancing antigen presentation on the tumor cell. Here, we identified MAL2 as a key player that determines the turnover of the antigen-loaded MHC-I complex and reduces the antigen presentation on tumor cells. MAL2 promotes the endocytosis of tumor antigens via direct interaction with the MHC-I complex and endosome-associated RAB proteins. In preclinical models, depletion of MAL2 in breast tumor cells profoundly enhanced the cytotoxicity of tumor-infiltrating [CD8.sup.+] T cells and suppressed breast tumor growth, suggesting that MAL2 is a potential therapeutic target for breast cancer immunotherapy., Introduction The immune system identifies and acts against tumor cells by adaptive cell reactions, which play a critical role in restricting tumor initiation and development. Cancer immunotherapy has become a [...]

Unlabelled: Although significant advances have been made in understanding the molecular mechanisms that influence tongue squamous cell carcinoma (TSCC) metastasis, less is known about the association between the cellular elastic modulus and TSCC metastasis. Atomic force microscopy (AFM) nanoindentation via the rate-jump method was used to detect the elastic modulus of TSCC cells from patients and cell lines with different metastatic potentials. TSCC cells with higher metastatic potential showed decreases in the elastic modulus compared to TSCC cells with lower metastatic potential. Moreover, the decrease in elastic modulus was accompanied with epithelial-mesenchymal transition (EMT), cytoskeleton (F-actin and β-tubulin) changes, small nucleus size and large nucleus/cytoplasm (N/C) ratio. The present findings demonstrate a close relationship between the cellular elastic modulus and the metastasis of TSCC. The elastic modulus detected by AFM nanoindentation via the rate-jump method can potentially be used to grade the metastatic potential of TSCC., From the Clinical Editor: This team of investigators report the use of an atomic force microscopy-based method to determine the elastic modulus of tongue squamous cell carcinoma cells, and demonstrate that such cells with higher metastatic potential show decreased elastic modulus compared to cells with lower metastatic potential., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The plasmodium of Physarum polycephalum is a suitable eukaryotic cell for cell cycle investigation, but there is no compatible transient expression system for the plasmodium. Using the promoter and terminator of ardC actin of Physarum polycephalum substituted the CMV IE and SV40 polyA of plasmid pDsRedl-N1, using cassette PardC-MCS-DsRed1-TardC substituted the cassette PardC-hph-TardC of plasmid pTB38, we constructed plasmids pXM1 and pXM2 for transient expression of red fluorescent protein (RFP) in Physarum polycephalum respectively. After reconstituting the transcription elongation factor homologous gene (pelf1) of Physarum polycephalum into the pXM2, we generated a plasmid pXM2-pelf1. After the plasmid pXM1, pXM2 and pXM2-pelf1 were electroporated into the plasmodium of Physarum polycephalum, we observed optimum RFP and PELF1-RFP expression under fluoroscope and confocal microscope between 24-48 h after electroporation, and found that ELF1-RFP expression was accumulated in nucleus of microplasmodium, the optimum electroporation parameters were 40 V/cm electric field, 1 ampere current, and 70 micros electric shock time. The results suggest that this expression system is qualified for transient expression of specific protein in plasmodium of Physarum polycephalum.