Boosting anti-tumor immunity in the omentum for metastasis prevention

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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.