Boosting anti-tumor immunity in the omentum for metastasis prevention

项目摘要/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袭。矛盾的是，大网膜是卵巢的主要部位 肿瘤转移和大网膜免疫细胞不能有效防御癌症的原因尚不清楚 细胞。由于转移到大网膜会导致严重的疼痛和肠梗阻，因此切除 有病的大网膜是护理的标准。另一方面，预防性摘除卵巢内的大网膜 没有明显转移的癌症患者一直存在争议，也没有普遍接受治疗。 然而，目前还没有有效的策略来防止隐匿性循环癌细胞转移到 当这个部位被保存时的大网膜。这项研究的目标是开发治疗策略，以促进 抗肿瘤免疫作用于大网膜，从而防止大网膜转移。我们的实验室以前 发现中性粒细胞是免疫防御的第一线，在转移和转移之前动员到大网膜。 将染色质纤维挤出，称为中性粒细胞胞外陷阱(Net)。我们最新的研究使用了基因 改良型Net缺陷小鼠暗示Net使大网膜“受精”以允许转移 通过刺激免疫抑制淋巴细胞的扩张。因此，我们假设用这种疗法 网络抑制剂增强了大网膜的抗肿瘤免疫，从而防止了大网膜转移。在……里面 在这项研究中，我们将首先建立并验证一个临床前模型，该模型概括了大网膜转移和 启用对免疫抑制淋巴细胞的跟踪。通过使用这个模型，我们将评估 净抑制药减少免疫抑制淋巴细胞池在大网膜，增强 PD-1靶向免疫治疗的有效性，并改善结果。如果成功，我们的研究可能会导致 未得到充分服务的卵巢癌患者人群的生活质量得到改善 大网膜转移。通过改变现有的网络抑制剂的用途，我们的研究可以加速预防 以及时、成本效益高、风险较小的方式预防大网膜转移。

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.