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1. chinaXiv:201605.01515 [pdf]

Intratumoral Delivery of IL-21 Overcomes Anti-Her2/Neu Resistance through Shifting Tumor-Associated Macrophages from M2 to M1 Phenotype

Xu, Meng; Liu, Mingyue; Du, Xuexiang; Li, Sirui; Li, Hang; Li, Xiaozhu; Li, Ying; Qin, Zhihai; Fu, Yang-Xin; Wang, Shengdian; Xu, Meng; Liu, Mingyue; Du, Xuexiang; Li, Sirui; Wang, Yang; Fu, Yang-Xin
Subjects: Biology >> Biophysics >> Immunology

Tumor resistance is a major hurdle to anti-Her2/neu Ab-based cancer therapy. Current strategies to overcome tumor resistance focus on tumor cell-intrinsic resistance. However, the extrinsic mechanisms, especially the tumor microenvironment, also play important roles in modulating the therapeutic response and resistance of the Ab. In this study, we demonstrate that tumor progression is highly associated with TAMs with immune-suppressive M2 phenotypes, and deletion of TAMs markedly enhanced the therapeutic effects of anti-Her2/neu Ab in a HER2/neu-dependent breast cancer cell TUBO model. Tumor local delivery of IL-21 can skew TAM polarization away from the M2 phenotype to a tumor-inhibiting M1 phenotype, which rapidly stimulates T cell responses against tumor and dramatically promotes the therapeutic effect of anti-Her2 Ab. Skewing of TAM polarization by IL-21 relies substantially on direct action of IL-21 on TAMs rather than stimulation of T and NK cells. Thus, our findings identify the abundant TAMs as a major extrinsic barrier for anti-Her2/neu Ab therapy and present a novel approach to combat this extrinsic resistance by tumor local delivery of IL-21 to skew TAM polarization. This study offers a therapeutic strategy to modulate the tumor microenvironment to overcome tumor-extrinsic resistance.

submitted time 2016-05-12 Hits2436Downloads1208 Comment 0

2. chinaXiv:201605.01420 [pdf]

A Vaccinia Virus Armed with Interleukin-10 Is a Promising Therapeutic Agent for Treatment of Murine Pancreatic Cancer

Chard, Louisa S.; Ahmed, Jahangir; El Khouri, Margueritte; Hughes, Jonathan; Lemoine, Nicholas R.; Wang, Yaohe; Maniati, Eleni; Hagemann, Thorsten; Wang, Pengju; Zhang, Zhongxian; Gao, Dongling; Wang, Jiwei; Cao, Fengyu; Lemoine, Nicholas R.; Wang, Yaohe; Wang, Shengdian; Li, Xiaozhu; Denes, Bela; Fodor, Istvan
Subjects: Biology >> Biophysics >> Oncology

Purpose: Vaccinia virus has strong potential as a novel therapeutic agent for treatment of pancreatic cancer. We investigated whether arming vaccinia virus with interleukin-10 (IL10) could enhance the antitumor efficacy with the view that IL10 might dampen the host immunity to the virus, increasing viral persistence, thus maximizing the oncolytic effect and antitumor immunity associated with vaccinia virus. Experimental Design: The antitumor efficacy of IL10-armed vaccinia virus (VVL Delta TK-IL10) and control VV Delta TK was assessed in pancreatic cancer cell lines, mice bearing subcutaneous pancreatic cancer tumors and a pancreatic cancer transgenic mouse model. Viral persistence within the tumors was examined and immune depletion experiments as well as immunophenotyping of splenocytes were carried out to dissect the functional mechanisms associated with the viral efficacy. Results: Compared with unarmed VVL Delta TK, VVL Delta TK-IL10 had a similar level of cytotoxicity and replication in vitro in murine pancreatic cancer cell lines, but rendered a superior antitumor efficacy in the subcutaneous pancreatic cancer model and a K-ras-p53 mutant-transgenic pancreatic cancer model after systemic delivery, with induction of long-term antitumor immunity. The antitumor efficacy of VVL Delta TK-IL10 was dependent on CD4(+) and CD8(+), but not NK cells. Clearance of VVL Delta TK-IL10 was reduced at early time points compared with the control virus. Treatment with VVL Delta TK-IL10 resulted in a reduction in virus-specific, but not tumor-specific CD8+ cells compared with VVL Delta TK. Conclusions: These results suggest that VVL Delta TK-IL10 has strong potential as an antitumor therapeutic for pancreatic cancer. (C) 2014 AACR.

submitted time 2016-05-12 Hits3392Downloads1129 Comment 0

3. chinaXiv:201605.01351 [pdf]

CD163+CD14+macrophages, a potential immune biomarker for malignant pleural effusion

Wang, Fei; Yang, Li; Gao, Qun; Huang, Lan; Zhang, Yi; Wang, Fei; Zhang, Yi; Gao, Qun; Wang, Liping; Zhang, Yi; Wang, Jing; Wang, Shengdian; Zhang, Bin
Subjects: Biology >> Biophysics >> Oncology

Malignant pleural effusion (MPE) is a common complication caused by malignant diseases. However, subjectivity, poor sensitivity, and substantial false-negative rates of cytology assay hamper accurate MPE diagnosis. The aim of this study was to assess whether CD163+CD14+ tumor-associated macrophages (TAMs) could be used as a biomarker for enabling sensitive and specific MPE diagnosis. Pleural effusion samples and peripheral blood samples were collected from 50 MPE patients and 50 non-malignant pleural effusion (NMPE) patients, respectively. Flow cytometry was performed to analyze cell phenotypes, and RT-qPCR was used to detect cytokine expression in these monocytes and macrophages. A blinded validation study (n = 40) was subsequently performed to confirm the significance of CD163+CD14+ TAMs in MPE diagnosis. Student's t test, rank sum test, and receiver operating characteristic curve analysis were used for statistical analysis. Notably, CD163+CD14+ cell frequency in MPE was remarkably higher than that in NMPE (P < 0.001). In a blinded validation study, a sensitivity of 78.9 % and a specificity of 100 % were obtained with CD163+CD14+ TAMs as a MPE biomarker. In total (n = 140), by using a cutoff level of 3.65 %, CD163+CD14+ cells had a sensitivity of 81.2 % and a specificity of 100 % for MPE diagnosis. Notably, MPE diagnosis by estimating CD163+CD14+ cells in pleural effusion could be obtained one week earlier than that obtained by cytological examination. CD163+CD14+ macrophages could be potentially used as an immune diagnostic marker for MPE and has better assay sensitivity than that of cytological analysis.

submitted time 2016-05-11 Hits3483Downloads1238 Comment 0

4. chinaXiv:201605.01295 [pdf]

Granzyme M expressed by tumor cells promotes chemoresistance and EMT in vitro and metastasis in vivo associated with STAT3 activation

Wang, Huiru; Wu, Yanhong; Zhou, Chunxia; Ma, Wenbo; Zhang, Youhui; Zhang, Shuren; Wang, Huiru; Wu, Yanhong; Zhou, Chunxia; Ma, Wenbo; Zhang, Youhui; Zhang, Shuren; Wang, Huiru; Wu, Yanhong; Wang, Lin; Zhou, Chunxia; Ma, Wenbo; Zhang, Youhui; Zhang, Shuren; Sun, Qing
Subjects: Biology >> Biophysics >> Oncology

Granzyme M is a serine protease known to be often expressed by natural killer cells and induce target cells apoptosis in combination with perforin. However, we detected granzyme M expression in murine and human cancer cell lines and human tumor samples in our study. Granzyme M increased chemoresistance, colony-formation, cytokine secretion and invasiveness in vitro. Most importantly, granzyme M facilitated tumor growth and metastasis in vivo. Granzyme M induced the epithelial-mesenchymal transition (EMT) in cancer cells associated with STAT3 activation. Our study revealed the role of granzyme M expressed by tumor in chemoresistance, invasion, metastasis and EMT.

submitted time 2016-05-11 Hits3148Downloads1042 Comment 0

5. chinaXiv:201605.00728 [pdf]

Expression of the galectin-9-Tim-3 pathway in glioma tissues is associated with the clinical manifestations of glioma

Liu, Zengjin; He, Xin; Li, Shouwei; Wu, Chenxing; Yu, Chunjiang; Han, Huamin; Wang, Shengdian;
Subjects: Biology >> Biophysics >> Oncology

Glioma is known to induce local and systemic immunosuppression, which inhibits antitumor T cell responses. The galectin-9-Tim-3-pathway negatively regulates T cell pathways in the tumor immunosuppressive environment. The present study assessed the expression of Tim-3 and galectin-9 in glioma patients, and evaluated the association between the expression of Tim-3 and galectin-9 with clinical characteristics. The present study identified that Tim-3 expression was significantly increased in peripheral blood T cells of glioma patients compared with those of healthy controls, and was additionally increased on tumor-infiltrating T cells. The expression of Tim-3 on tumor-infiltrating T cells was associated with the World Health Organization (WHO) grade of glioma, but negatively correlated with the Karnofsky Performance Status score of the glioma patients. Immunohistochemical analysis revealed that the expression of galectin-9 in tumor tissues was associated with Tim-3 expression on tumor-infiltrating T cells and the WHO grade of glioma. These findings suggest that the galectin-9-Tim-3 pathway may be critical in the immunoevasion of glioma and may be a potent target for immunotherapy in glioma patients.

submitted time 2016-05-05 Hits1186Downloads617 Comment 0

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