PDF file - 221K, Supplemental Figs: 1. Transformation of VNP20009 with shIDO does not enhance its infectivity 2. ShIDO-ST reduces the formation of melanoma lung metastases. 3. Frequency of Gr1+CD11b+ cells in organs of tumor-bearig mice receiving PBS, shScr-ST, or shIDO-ST treatment. 4. Apoptotic CD45+ subsets in tumors of shIDO-ST treated mice includes CD4+ and CD8+ cells. 5. Hypoxia alone does not induce apoptosis in shIDO-ST-infected B16F10 cells. 6. ShIDO-ST treatment suppresses subcutaneous (s.c.) Pan02 tumor growth in C57BL/6 mice. Supplemental Methods: Flow cytometry and statistics
ARTICLE ABSTRACT
Generating antitumor responses through the inhibition of tumor-derived immune suppression represents a promising strategy in the development of cancer immunotherapeutics. Here, we present a strategy incorporating delivery of the bacterium Salmonella typhimurium (ST), naturally tropic for the hypoxic tumor environment, transformed with a small hairpin RNA (shRNA) plasmid against the immunosuppressive molecule indoleamine 2,3-dioxygenase 1 (shIDO). When systemically delivered into mice, shIDO silences host IDO expression and leads to massive intratumoral cell death that is associated with significant tumor infiltration by polymorphonuclear neutrophils (PMN). shIDO-ST treatment causes tumor cell death independently of host IDO and adaptive immunity, which may have important implications for use in immunosuppressed patients with cancer. Furthermore, shIDO-ST treatment increases reactive oxygen species (ROS) produced by infiltrating PMNs and, conversely, PMN immunodepletion abrogates tumor control. Silencing of host IDO significantly enhances S. typhimurium colonization, suggesting that IDO expression within the tumor controls the immune response to S. typhimurium. In summary, we present a novel approach to cancer treatment that involves the specific silencing of tumor-derived IDO that allows for the recruitment of ROS-producing PMNs, which may act primarily to clear S. typhimurium infection, but in the process also induces apoptosis of surrounding tumor tissue resulting in a vigorous antitumor effect. Cancer Res; 72(24); 6447–56. ©2012 AACR.
