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1. chinaXiv:202101.00036 [pdf]

Targeting pan-tumor antigens to activating Fcγ receptors generates a novel dendritic cell tumor vaccine

Sheng, Hui; Wnag, Pan; Zhang, Guoxiu; Zhang, Xiao; Li, Zhongjun; Zhao, Zhihui
Subjects: Medicine, Pharmacy >> Preclinical Medicine

Objective: Therapeutic tumor vaccines are eagerly awaited in clinic by patients with high expectations; however, very few clinically successful tumor vaccine has been developed thus far, and there remains no consensus on the generation of tumor vaccines. We hypothesized that targeted delivery of pan-tumor antigens instead of individual tumor-associated antigen (TAA) to dendritic cells via the activating receptor endocytic pathway (AREP) would provide an alternative avenue to develop potent personalized tumor vaccines. Methods: We first prepared biotin-tagged tumor antigens (B-TAgs) with mouse CT26. WT colorectal cancer cells by exploiting metabolic glycan labeling and bioorthogonal reaction methods; then, we prepared a bifunctional fusion protein containing streptavidin and a mouse IgG2a Fc fragment (SA-Fc), in which streptavidin was used for conjugation with B-TAgs, and Fc for mediating the interaction with the Fcγ receptor. Finally, conjugates (Fc-TAgs) of SA-Fc with B-TAgs were prepared based on affinity-guided noncovalent reaction. The phenotype of Fc-TAgs pulsed bone marrow-derived dendritic cells (BMDCs) was examined by flow cytometry. The therapeutic effects of Fc-TAgs pulsed BMDCs were observed in an established mouse CT26. WT colorectal cancer model. Results: The prepared B-TAgs covers almost all glycosylated tumor antigens. SA-Fc fusion protein exhibits biotin-binding activity as a homodimer. SA-Fc can effectively conjugate with B-TAg at a mixing ratio of 1:96 (w/w). Data of flow cytometry revealed that on Fc-TAgs pulsed BMDCs, the expression levels of surface molecules, such as CD80 and MHC II, were greatly increased. In the established murine colorectal cancer model, combination treatments with Fc-TAgs pulsed BMDCs and PD-1 blockade achieved significant therapeutic effects. Limitations: The strategy we proposed for the preparation of personalized tumor vaccine requires that the tumor be surgically removed from the patient. The rationality and validity of this strategy need to be proven by more preclinical investigations. Conclusions: The novel strategy we proposed circumvents the necessities for neoantigen prediction and provides an alternative pathway to establish a flexible system for the preparation of personalized dendritic cell tumor vaccines. In the setting of checkpoint blockade-based immunotherapy, a novel DCV would improve antitumor immunity and benefit the eradication of tumor residues within the body of the cancer patients.

submitted time 2021-01-07 Hits11907Downloads1246 Comment 0

2. chinaXiv:201605.01740 [pdf]

Aberrantly upregulated TRAP1 is required for tumorigenesis of breast cancer

Zhang, Bo; Wei, Peng; Hao, Junfeng; Zhao, Lijing; Zhang, Fenglin; Wei, Taotao; Wang, Jing; Huang, Zhen; Wei, Peng; Liu, Ying; Tu, Yaping
Subjects: Biology >> Biophysics >> Oncology

Tumor necrosis factor receptor-associated protein 1 (TRAP1) is abnormally expressed in many cancers. In this study, we showed that TRAP1 is aberrantly upregulated in breast tumors compared to control tissues. TRAP1 knockdown downregulates mitochondrial aerobic respiratory, sensitizes cells to lethal stimuli, and inhibited tumor growth in MDA-MB-231 and MCF-7 breast cancer cells in vivo. TRAP1 overexpression, however, enhances the capacity to cope with stress conditions. These evidences suggested that TRAP1 is required for tumorigenesis. We also found that TRAP1 regulates the mitochondrial morphology. Relatively lower TRAP1 levels are associated with the rod-shaped mitochondrial phenotype in invasive and metastatic MDA-MB-231 breast cancer cells; on the contrary, higher TRAP1 levels are associated with the tubular network-shaped mitochondrial phenotype in non-invasive MCF-7 cells. Interestingly, the expression of TRAP1 in human breast cancer specimens inversely correlates with tumor grade. Overexpression of TRAP1 in MDA-MB-231 cells causes mitochondrial fusion, triggers mitochondria to form tubular networks, and suppresses cell migration and invasion in vitro and in vivo. These data link TRAP1-regulated mitochondrial dynamics and function with tumorigenesis of breast cancer and suggested that TRAP1 may therefore be a potential target for breast cancer drug development.

submitted time 2016-05-15 Hits4274Downloads1774 Comment 0

3. chinaXiv:201605.01245 [pdf]

Serial in Vivo Imaging Using a Fluorescence Probe Allows Identification of Tumor Early Response to Cetuximab Immunotherapy

Ma, Teng; Liu, Hao; Sun, Xianlei; Gao, Liquan; Shi, Jiyun; Zhao, Huiyun; Jia, Bing; Wan, Fan; Liu, Zhaofei; Ma, Teng; Liu, Hao; Sun, Xianlei; Gao, Liquan; Jia, Bing; Wan, Fan; Liu, Zhaofei; Shi, Jiyun; Zhao, Huiyun
Subjects: Biology >> Biophysics

Cetuximab is an antiepidermal growth factor receptor (EGFR) monoclonal antibody that has received the approval of the Food and Drug Administration (FDA) for cancer treatment. However, most clinical studies indicate that cetuximab can only elicit positive effects on a subset of cancer patients. In this study, we investigated whether near-infrared fluorescence (NIRF) imaging of tumor vascular endothelial growth factor (VEGF) expression could be a biomarker for tumor early response to cetuximab therapy in preclinical wild-type and mutant tumor models of the KRAS gene. The treatment efficacy of cetuximab was determined in both HT-29 (wild-type KRAS) and HTC-116 (mutant KRAS) human colon cancer models. A VEGF-specific optical imaging probe (Dye755-Ran) was synthesized by conjugating ranibizumab (an anti-VEGF antibody Fab fragment) with a NIRF dye. Serial optical scans with Dye755-Ran were performed in HT-29 and HTC-116 xenograft models. By using longitudinal NIRF imaging, we were able to detect early tumor response on day 3 and day 5 after initiation of cetuximab treatment in the cetuximab-responsive HT-29 tumor model. Enzyme-linked immunosorbent assay (ELISA) confirmed that cetuximab treatment inhibited human VEGF expression in the KRAS wild-type HT-29 tumor but not in the KRAS mutant HCT-116 tumor. We have demonstrated that the antitumor effect of cetuximab can be noninvasively monitored by serial fluorescence imaging using Dye755-Ran. VEGF expression detected by optical imaging could serve as a sensitive biomarker for tumor early response to drugs that directly or indirectly act on VEGF.

submitted time 2016-05-11 Hits1996Downloads1072 Comment 0

4. chinaXiv:201605.00771 [pdf]

Screening and identification of post-traumatic stress-related serum factors in children with Wilms' tumors

Zhang, Junjie; Guo, Fei; Wang, Lei; Zhao, Wei; Zhang, Da; Yang, Heying; Wang, Jiaxiang; Hu, Qian; Yu, Jiekai; Zheng, Shu; Niu, Lili; Yang, Fuquan;
Subjects: Biology >> Biophysics >> Oncology

Wilms' tumors are one of the most common malignant, solid intra-abdominal tumors observed in children. Although potential tumor markers have been found, inflammatory cytokines interfere with the process of specific protein identification. The present study was undertaken to identify post-traumatic stress-related factors of Wilms' tumors and to verify the accuracy of early-stage tumor-specific serum protein markers. Serum samples were screened for differentially-expressed proteins using surface-enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF-MS). Potential markers were isolated and purified using solid-phase extraction (SPE) and SDS-PAGE. Following enzymatic digestion of the protein samples, the peptide fragments were detected with high performance liquid chromatography-mass spectrometry. The obtained peptide mass fingerprint was searched in the Swiss-Prot protein sequence database via the Mascot search engine. Differentially-expressed proteins were verified using western blot analysis. Differentially-expressed proteins with a mass/charge of 5,816 were screened out using SELDI-TOF-MS, and significant differences between the tumor and control groups, and the trauma and control groups were observed. Target proteins were isolated and purified using SPE and SDS-PAGE. Thioredoxin 1 (Trx1) was found to be differentially expressed. In the serum of children with Wilms' tumors, there was an increase in the level of the post-traumatic stress-related inflammatory factor, Trx1, as compared with the normal control group. Thus, the results of this study indicate that Trx1 presents a potential post-traumatic stress-related factor of Wilms' tumors.

submitted time 2016-05-05 Hits1755Downloads969 Comment 0

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