Type I Interferon Regulation of Tumor Cell and Immune Cell Interaction in Human Colon Cancer

点击翻译按钮获取中文摘要

Project Summary IFN was an FDA-approved agent for human cancer therapy and is currently used as exogenous recombinant protein or protein prodrugs. The use of IFN in human cancer therapy has been limited by the ineffective dosing and high toxicity. This proposal develops a lipid nanoparticle encapsulated IFN-encoding DNA nanoplasmid (IFNA13CO01) to force tumor cells to express and produce endogenous IFN13 locally in the tumor microenvironment. IFNA13CO01 therapy is therefore expected to produce high level of endogenous IFN13 locally in the tumor site and thus overcomes the ineffective dosing and systemic toxicity issues associated with the current IFN agents. In the preliminary studies, we determined that type I interferon (IFN-I: IFN and IFN) expression level is significantly lower in human colorectal carcinoma than in normal colon tissue. We further determined that IFN-I functions in both tumor cells and T cells are essential for host cancer immune surveillance. Mechanistically, we determined that IFN-I activates STAT3 that binds to the Gzmb promoter to activate Gzmb transcription in CTLs. The IFN-I/STAT3/Gzmb axis thus is essential for CTL anti- tumor function. In addition, we determined that tumor cell expressed PD-L1 (tPD-L1) engages myeloid cell expressed PD-1 (mPD-1) to antagonize IFN-I and STAT1 signaling to repress Cxcl9 and Cxcl10 to impair CTL recruitment to lung metastases. Human patient response to PD-1 blockade immunotherapy correlates with IFN-I response in myeloid cells. We therefore discovered that the tPD-L1/mPD-1/IFN-I/STAT1/Cxcl9-Cxcl10 axis controls CTL tumor infiltration in lung metastasis. Our central hypothesis is that forcing tumor cells to express and produce endogenous IFN13 in the local tumor microenvironment via IFNA13CO01 therapy is an effective and yet safe approach to suppress human colorectal tumor growth and progression. We propose to test our new central hypothesis by pursuing the following 3 specific aims: 1) Test the hypothesis that tPD-1 engages mPD-1 to inhibit IFI-I signaling to suppress CTL recruitment and function to promote metastatic tumor growth in human colon cancer patients.; 2) Determine the efficacy of IFNA13CO01 in suppression of metastatic human colon cancer PDX growth in humanized NSG mice; and 3) Determine IFNA13CO01 biodistribution, toxicology and pharmacokinetics in vivo.