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

项目摘要 干扰素是fda批准的用于人类癌症治疗的药物，目前被用作外源性 重组蛋白质或蛋白质前药。干扰素在人类癌症治疗中的使用受到 用药效率低，毒性大。该方案开发了一种包裹干扰素编码的脂质纳米颗粒 诱导肿瘤细胞局部表达和产生内源性干扰素-13的研究 肿瘤微环境。因此，IFNA13CO01治疗有望产生高水平的内源性 干扰素13定位于肿瘤部位，从而克服了无效剂量和全身毒性问题 与目前的干扰素试剂有关。在初步研究中，我们确定I型干扰素(干扰素-I： 干扰素和干扰素在结直肠癌组织中的表达水平显著低于正常结肠组织 组织。我们进一步确定，肿瘤细胞和T细胞中的干扰素-I功能对宿主癌症是必不可少的 免疫监视。从机制上，我们确定了干扰素-I激活了与Gzmb结合的STAT3 激活CTL中Gzmb转录的启动子。因此，干扰素-I/STAT3/Gzmb轴对于CTL抗-HBs是必不可少的。 肿瘤功能。此外，我们还确定了表达PD-L1(tpd-L1)的肿瘤细胞与髓系细胞结合 表达PD-1(MPD-1)以拮抗干扰素-I和STAT1信号以抑制Cxcl9和Cxcl10以损害CTL 募集到肺转移瘤。人类患者对PD-1阻断免疫治疗的反应与 髓系细胞的干扰素-I反应。因此，我们发现TPD-L1/MPD-1/干扰素-I/STAT1/CxCl9-CxCl10 Axis控制CTL肿瘤在肺转移中的侵袭。我们的中心假设是迫使肿瘤细胞 通过IFNA13CO01治疗在局部肿瘤微环境中表达和产生内源性干扰素13 抑制人类结直肠肿瘤生长和进展的有效且安全的方法。我们建议 通过追求以下三个具体目标来测试我们的新中心假设：1)测试TPD-1的假设 利用MPD-1抑制IFI-I信号，抑制CTL募集并促进肿瘤转移 2)确定IFNA13CO01抑制人结肠癌患者生长的有效性。 人源化NSG小鼠体内转移性人结肠癌PDX生长；3)检测IFNA13CO01 体内生物分布、毒理学和药代动力学。

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.