Boosting anti-tumor immunity in the omentum for metastasis prevention

增强大网膜的抗肿瘤免疫力以预防转移

• 批准号: 10648192
• 负责人: Honami Naora
• 金额: $ 18.93万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-02 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648192
• 关键词: Acceleration; Address; Adipose tissue; Attention; B-Lymphocytes; Cancer Patient; Cells; Cellular Structures; Chromatin Fiber; Clinical; Clinical Management; Data; Development; Disease; Disease Progression; Effectiveness; Excision; Exhibits; Goals; Greater sac of peritoneum; Immune; Immune Tolerance; Immunity; Immunosuppression; Immunotherapy; Implant; Infection; Interleukin-10; Internet; Intestinal Obstruction; Laboratories; Lymphocyte; Malignant neoplasm of ovary; Modeling; Mus; Neoplasm Metastasis; Omentum; Pain; Peritoneal; Peritoneal Fluid; Play; Positioning Attribute; Pre-Clinical Model; Prevention; Production; Quality of life; Regimen; Regulatory T-Lymphocyte; Reporter; Risk; Role; Sepsis; Signal Transduction; Site; Spottings; Stomach; Surface; T-Lymphocyte; Th1 Cells; Therapeutic; Tumor Immunity; Underserved Population; Validation; Work; anti-PD1 therapy; cancer cell; cancer therapy; cancer type; chemotherapy; circulating cancer cell; cost effective; extracellular; improved outcome; in vivo; inhibitor; innovation; insight; interest; metastasis prevention; neutrophil; novel strategies; ovarian neoplasm; pathogen; permissiveness; preservation; prevent; programmed cell death protein 1; prophylactic; response; standard of care; targeted treatment; therapy development; tumor; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT The omentum is an immune cell-rich fatty tissue that suspends from the stomach and plays an important role in defending the peritoneal cavity against pathogens. Paradoxically, the omentum is the major site of ovarian cancer metastasis and it is unclear why immune cells in the omentum do not effectively defend against cancer cells. Because metastasis to the omentum can cause substantial pain and bowel obstruction, removal of the diseased omentum is the standard-of-care. On the other hand, prophylactic removal of the omentum in ovarian cancer patients who do not present with overt metastasis has been contentious and not universally performed. However, there are currently no effective strategies to prevent metastasis of occult circulating cancer cells to the omentum when this site is preserved. The goal of this study is to develop therapeutic strategies that boost anti-tumor immunity in the omentum and thereby prevent omental metastasis. Our laboratory has previously identified that neutrophils, the first-line of immune defense, mobilize into the omentum prior to metastasis and extrude chromatin fibers called neutrophil extracellular traps (NETs). Our more recent studies using genetically modified NET-deficient mice implicate that NETs `fertilize' the omentum to become permissive for metastasis by stimulating expansion of immunosuppressive lymphocytes. We therefore hypothesize that treatment with NET-inhibiting agents boosts anti-tumor immunity in the omentum and thereby prevents omental metastasis. In this study, we will firstly establish and validate a preclinical model that recapitulates omental metastasis and enables tracing of immunosuppressive lymphocytes. By using this model, we will then evaluate the ability of NET-inhibiting agents to decrease the pool of immunosuppressive lymphocytes in the omentum, enhance the effectiveness of PD-1-targeted immunotherapy, and improve outcomes. If successful, our study could lead to better quality-of-life in an underserved population of ovarian cancer patients who initially present without overt omental metastasis. By repurposing available NET-inhibiting agents, our study could accelerate the prevention of omental metastasis in a timely and cost-effective manner and with fewer risks.

项目概要/摘要 大网膜是一种富含免疫细胞的脂肪组织，悬挂在胃中，在 保护腹膜腔免受病原体侵害。矛盾的是，大网膜是卵巢的主要部位 癌症转移，目前尚不清楚为什么大网膜中的免疫细胞不能有效防御癌症 细胞。由于转移至大网膜可引起剧烈疼痛和肠梗阻，因此切除网膜 患病的大网膜是标准治疗方法。另一方面，预防性切除卵巢内的大网膜 没有明显转移的癌症患者一直存在争议，并且并未普遍进行。 然而，目前尚无有效的策略来预防隐匿性循环癌细胞转移至癌症。 保留该部位时的大网膜。这项研究的目的是开发治疗策略，以促进 增强大网膜的抗肿瘤免疫力，从而预防大网膜转移。我们实验室此前曾 发现中性粒细胞是免疫防御的第一线，在转移之前动员到大网膜中，并且 挤出称为中性粒细胞胞外陷阱（NET）的染色质纤维。我们最近的研究使用基因 修饰的 NET 缺陷小鼠表明 NET 使大网膜“受精”，从而允许转移 通过刺激免疫抑制淋巴细胞的扩增。因此我们假设治疗 NET抑制剂可增强大网膜的抗肿瘤免疫力，从而防止大网膜转移。在 在这项研究中，我们将首先建立并验证一个能够概括大网膜转移和 能够追踪免疫抑制淋巴细胞。通过使用这个模型，我们将评估 NET 抑制剂可减少大网膜中免疫抑制淋巴细胞的数量，增强 PD-1靶向免疫疗法的有效性，并改善结果。如果成功的话，我们的研究可能会导致 在服务不足的卵巢癌患者群体中获得更好的生活质量，这些患者最初没有明显的表现 大网膜转移。通过重新利用现有的 NET 抑制剂，我们的研究可以加速预防 及时、经济有效且风险较小的大网膜转移。