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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 Hits3391Downloads1129 Comment 0

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