Inter-regulatory function of immune-modulation and angiogenesis in cancer

癌症中免疫调节和血管生成的相互调节功能

• 批准号: 9177165
• 负责人: GABRIELE BERGERS
• 金额: $ 36.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9177165
• 关键词: Angiogenesis Inhibitors; Angiogenic Factor; Blood Vessels; CD8B1 gene; CXCL14 gene; Cell Death; Cells; Clinic; Cytotoxic T-Lymphocytes; Dendritic Cells; Environment; Exhibits; Fostering; Goals; Growth; High Endothelial Venule; Immune; Immune system; Immunologic Surveillance; Immunosuppression; Infiltration; Inflammation; Inflammatory Response; KDR gene; Lesion; Lymphocyte; Malignant - descriptor; Malignant Neoplasms; Mediating; Modeling; Myelogenous; Myeloid Cells; Neoplasm Metastasis; PDCD1LG1 gene; PIK3CG gene; Pathway interactions; Phenotype; Population; Process; Protein Isoforms; Publishing; Recruitment Activity; Regulation; Relapse; Resistance; Signal Pathway; Signal Transduction; Source; T-Lymphocyte; Testing; Therapeutic; Up-Regulation; Vascular Endothelial Growth Factors; angiogenesis; base; bevacizumab; chemokine; cytokine; cytotoxic; immunoregulation; inhibitor/antagonist; neoplastic cell; neovascularization; pre-clinical; prevent; resistance mechanism; response; success; targeted cancer therapy; tissue repair; trafficking; tumor; tumor progression

PROJECT SUMMARY There is mounting evidence that tumors recruit various innate immune cells where they become an additional source of chemokines and cytokines to promote angiogenesis, invasion and metastasis as demonstrated in numerous preclinical tumor models. Importantly, like wounds, tumors attract innate immune cells that, rather than promoting the cytotoxic clearance of tumor cells, become immune-suppressive and angiogenic and elicit a tumor-promoting inflammatory response. In lieu of the fact that the regulation of angiogenesis and immunosuppression coincides in myeloid cells, one goal of this proposal is to test the hypothesis that the efficacy of antiangiogenic therapy hinges on fostering an immune-stimulatory environment and that concurrent use of immunomodulating molecules and agents can prevent or reverse resistance to angiogenic inhibitors leading to a more durable response to therapy. Based on our published and preliminary results, we further propose that blocking VEGF signaling promotes immune stimulation by altering the tumor vasculature to allow lymphocyte infiltration into the tumor and by polarizing immune cells to an Th1 phenotype by which they enhance the secretion of the chemokine CXCL14 blocking vessel sprouting and supporting the maturation of dendritic cells. In response, tumors enhance the secretion of factors that activate the PI3K and other immune- modulating pathway in myeloid cells restating an immune-suppressive and proangiogenic phenotype in myeloid cells that renders them non-responsive to antiangiogenic therapy and generates a proangiogenic tumor relapse. As a the first goal we intend to elicit the functional significance of the induction of CXCL14 in myeloid-driven tumor response as well as the induction of PDL1 and other immuneregulatroy pathways (e.g. Stat3 and NFkB pathways) factors in tumor relapse to antiangiogenic therapy. The second goal of this study will be then to therapeutically induce an enduring immunestimulating tumor environment by polarizing immune cells and modulating the tumor vessels to become reminiscent of high-endothelial venules that are specialized to promote lymphocyte trafficking. We propose that this will enable sufficient infiltration of activated cytotoxic T- cells and more sufficiently eradicate tumors and metastases.

项目摘要 越来越多的证据表明，肿瘤招募各种先天免疫细胞，使它们成为额外的免疫细胞。 促进血管生成、侵袭和转移的趋化因子和细胞因子的来源， 许多临床前肿瘤模型。重要的是，像伤口一样，肿瘤会吸引先天免疫细胞， 而不是促进肿瘤细胞的细胞毒性清除，成为免疫抑制和血管生成， 肿瘤促进炎症反应。事实上，血管生成的调节和 免疫抑制在髓系细胞中一致，该提议的一个目标是检验免疫抑制在髓系细胞中一致的假设。 抗血管生成治疗的功效取决于培养免疫刺激环境， 使用免疫调节分子和试剂可以防止或逆转对血管生成抑制剂的抗性 从而对治疗产生更持久的反应。根据我们公布的初步结果，我们进一步 提出阻断VEGF信号通过改变肿瘤血管系统促进免疫刺激， 淋巴细胞浸润到肿瘤中，并通过将免疫细胞极化为Th1表型， 增强趋化因子CXCL 14的分泌，阻断血管出芽并支持血管成熟， 树突状细胞作为回应，肿瘤增强了激活PI3K和其他免疫调节因子的分泌。 在骨髓细胞中的调节途径，重申免疫抑制和促血管生成表型， 骨髓细胞，使它们对抗血管生成治疗无反应，并产生促血管生成的 肿瘤复发 作为第一个目标，我们打算引出CXCL 14诱导在骨髓驱动的细胞中的功能意义。 肿瘤应答以及诱导PDL 1和其他免疫调节途径（例如，Stat3和NF κ B 途径）因素在肿瘤复发的抗血管生成治疗。本研究的第二个目标是， 通过极化免疫细胞治疗性地诱导持久的免疫估计肿瘤环境， 调节肿瘤血管，使其成为高内皮微静脉， 促进淋巴细胞运输。我们认为，这将使活化的细胞毒性T细胞充分浸润， 细胞和更充分地根除肿瘤和转移。