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.

项目摘要/摘要 omentum是一种富含免疫细胞的脂肪组织，可从胃中悬浮并在 捍卫腹膜腔抵抗病原体。自相矛盾的是，omentum是卵巢的主要地点 癌症转移，目前尚不清楚为什么omentum中的免疫细胞不能有效防御癌症 细胞。因为向大脑转移会导致严重的疼痛和肠梗阻，所以去除 患病的omentum是护理标准。另一方面，预防卵巢中的小膜的去除 不出现明显转移的癌症患者是有争议的，并且没有普遍表现。 但是，目前尚无有效的策略来防止神秘循环癌细胞转移 保留此站点时的omentum。这项研究的目的是制定促进治疗策略 大脑中的抗肿瘤免疫，从而防止粘膜转移。我们的实验室以前有 确定中性粒细胞是免疫防御的一线，在转移之前动员到脑类 挤出的染色质纤维称为中性粒细胞外陷阱（NET）。我们最近使用基因的研究 修饰的净缺陷小鼠暗示净拟网囊泡成为转移的允许 通过刺激免疫抑制淋巴细胞的扩张。因此，我们假设使用 网络抑制剂可以增强omentum中的抗肿瘤免疫力，从而防止粘膜转移。在 这项研究，我们将首先建立并验证一个概括性转移和的临床前模型 可以追踪免疫抑制淋巴细胞。通过使用此模型，我们将评估 抑制网状剂，以减少大脑中免疫抑制淋巴细胞的池，增强 PD-1靶向免疫疗法的有效性，并改善预后。如果成功，我们的研究可能会导致 在服务不足的卵巢癌患者中，最初没有明显的卵巢癌患者的生活质量更好 瘤转移。通过重新利用可用的网络抑制剂，我们的研究可以加速预防 及时且具有成本效益的方式，风险更少。