Prevention of Omental Metastasis of Ovarian Cancer by Targeting a Linkage Between Innate and Adaptive Immunity
Abstract
The omentum is a fatty tissue that suspends from the stomach, and is the predominant site of ovarian cancer metastasis. Metastasis to the omentum angulates the bowel, which causes substantial pain and bowel obstruction, a leading cause of death in women with ovarian cancer. Whereas removal of the diseased omentum is unquestionable, the removal of an otherwise healthy omentum has been contentious. One school of thought has advocated removal of the omentum as a preventative measure for women with early-stage ovarian cancer who do not present with omental metastasis. Because the omentum has an important function in protecting the abdominal cavity, a second school of thought has advocated preserving the uninvolved omentum to minimize complications caused by its removal. However, there are currently no effective strategies to prevent metastasis of occult (i.e., hidden) circulating ovarian cancer cells to the omentum when this site is preserved. The protective function of the omentum was recognized more than 100 years ago when it was described as the abdominal policeman. A unique feature of the omentum is its abundance of specialized clusters of immune cells that play an essential role in defending the abdominal cavity against infection. However, it is not clear why immune cells in the omentum do not effectively defend against metastatic ovarian cancer cells. The goal of this study is to identify why immune cells in the omentum do not mount effective responses against metastatic ovarian cancer cells, with the ultimate goal of developing approaches that can boost anti-tumor immunity in the omentum and thereby prevent metastasis of occult circulating cancer cells to the omentum when this site is preserved. Neutrophils are the most abundant type of circulating white blood cell and act as the first line of immune defense. In a previous study, our laboratory identified that neutrophils respond to early-stage ovarian tumors by mobilizing into the omentum and releasing sticky webs of DNA fibers called neutrophil extracellular traps (NETs) before metastasis occurs. Furthermore, we identified that NETs promote omental metastasis. In preliminary studies, we identified that another population of white blood cells, specifically an immunosuppressive type of B cell, normally increases in the omentum before metastasis, but does not increase in ovarian tumor-bearing, genetically modified mice that are deficient in NETs. We therefore propose that the inability of the omentum to mount effective responses against ovarian cancer cells occurs before metastasis and that this immune dysfunction stems from NET-induced expansion of immunosuppressive B cells. In this study, we will first determine whether expansion of B cells with immunosuppressive properties occurs in the omentum prior to metastasis and thereby primes the omentum for metastasis. Second, we will determine whether and how NETs cause immunosuppressive B cells to expand in the omentum. Third, we will determine whether pharmacologic inhibition of NETs suppresses expansion of immunosuppressive B cells and thereby prevents omental metastasis. We will accomplish these aims by a combination of approaches that include analyses of clinical specimens of human omentum, our genetically modified NET-deficient mouse model and new-generation mouse models, plus state-of-the-art single cell analysis and evaluation of NET-inhibiting agents.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210122
Entities
People
- Honami Naora
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army