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

I 型干扰素对人结肠癌肿瘤细胞和免疫细胞相互作用的调节

• 批准号: 10590049
• 负责人: KEBIN LIU
• 金额: --
• 依托单位: CHARLIE NORWOOD VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590049
• 关键词: Antigens; Binding; Biochemical; Biodistribution; Bone Marrow; Cell Communication; Chimera organism; Codon Nucleotides; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Colorectal Neoplasms; Cytotoxic T-Lymphocytes; DNA; Development; Dose; Drug Kinetics; Encapsulated; Exhibits; FDA approved; Funding; Gene Expression Profiling; General Population; Genetic Transcription; Growth; Human; IFNAR1 gene; Immune; Immunocompetent; Immunologic Surveillance; Immunotherapy; Impairment; Infiltration; Interferon Type I; Knock-out; Knockout Mice; Large Intestine Carcinoma; Ligands; Liposomes; Lung; Lymphocyte Activation; Lytic; Malignant Neoplasms; Metastatic Neoplasm to the Liver; Metastatic Neoplasm to the Lung; Molecular; Mus; Myeloid Cells; Neoplasm Metastasis; PD-1 blockade; PD-1/PD-L1; Pathway interactions; Primary Neoplasm; Prodrugs; Productivity; Proteins; RNA; Recombinant Proteins; Regulation; Repression; Research Design; Resistance; Role; STAT1 gene; STAT3 gene; Signal Transduction; Site; Survival Rate; T-Lymphocyte; Testing; Tissues; Toxic effect; Toxicology; Tumor Escape; Tumor-Infiltrating Lymphocytes; Veterans; aged; anti-PD-1; cancer immunotherapy; cancer therapy; colon cancer metastasis; colon cancer patients; colon cancer treatment; design; efficacy evaluation; genome-wide; in vivo; lipid nanoparticle; mortality; mouse model; neoplastic cell; patient derived xenograft model; patient response; programmed cell death ligand 1; programmed cell death protein 1; promoter; reconstitution; recruit; response; single-cell RNA sequencing; systemic toxicity; tumor; tumor growth; tumor microenvironment; tumor progression; type I interferon receptor

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.

项目摘要 IFN γ是FDA批准的用于人类癌症治疗的药剂，并且目前用作外源性 重组蛋白或蛋白前药。IFN γ在人类癌症治疗中的使用受到了限制， 给药无效且毒性高。该提案开发了脂质纳米颗粒包封的IFN γ编码的 DNA纳米质粒（IFNA 13 CO 01）迫使肿瘤细胞局部表达并产生内源性IFN-γ 13 肿瘤微环境。因此，预期IFNA 13 CO 01疗法产生高水平的内源性TNF-α。 IFN γ 13局部在肿瘤部位，因此克服了无效给药和全身毒性问题 与目前的IFN γ药物有关。在初步研究中，我们确定I型干扰素（IFN-I： IFN γ和IFN γ在大肠癌中的表达水平明显低于正常大肠组织 组织.我们进一步确定，IFN-Ⅰ在肿瘤细胞和T细胞中的功能对于宿主癌症是必需的， 免疫监视从机制上讲，我们确定IFN-I激活了与Gzmb结合的STAT 3， 启动子激活CTL中的Gzmb转录。因此，IFN-1/STAT 3/Gzmb轴对于CTL抗Gzmb是必需的。 肿瘤功能此外，我们确定肿瘤细胞表达的PD-L1（tPD-L1）与髓系细胞 表达PD-1（mPD-1），拮抗IFN-1和STAT 1信号传导，抑制Cxcl 9和Cxcl 10，损害CTL 肺转移的招募。人类患者对PD-1阻断免疫疗法的反应与以下因素相关： 骨髓细胞中的IFN-I应答。因此，我们发现tPD-L1/mPD-1/IFN-I/STAT 1/Cxcl 9-Cxcl 10 轴控制CTL肿瘤浸润在肺转移。我们的中心假设是迫使肿瘤细胞 通过IFNA 13 CO 01疗法在局部肿瘤微环境中表达和产生内源性IFN β 13是一种有效的治疗方法。 有效且安全的方法来抑制人结肠直肠肿瘤生长和进展。我们建议 通过追求以下3个具体目标来测试我们新的中心假设：1）测试tPD-1 结合mPD-1以抑制IFI-I信号传导，从而抑制CTL募集并发挥促进转移性肿瘤的功能 结肠癌病人的生长。2)确定IFNA 13 CO 01在抑制肿瘤细胞增殖中的功效。 人源化NSG小鼠中的转移性人结肠癌PDX生长;和3）测定IFNA 13 CO 01 体内生物分布、毒理学和药代动力学。