Immune Checkpoint Regulator in Ovarian Cancer Progression
Abstract
Advanced ovarian cancer (stages III and IV) accounts for most of the approximately 20,000 yearly new cases of epithelial ovarian cancer in the United States. Over 16,000 deaths per year in the United States are due to ovarian cancer, making it the most lethal gynecologic malignancy. No major strides have been made over the past decade to improve the survival of patients with advanced ovarian cancer. Ovarian cancer, in particular, high-grade serous ovarian cancer (HGSOC), is notable for initial chemosensitivity, with response rates >75% to combination platinum and taxane chemotherapy following debulking surgery in HGSOC. While a vast majority of patients with HGSOCs have their cancers recur within 12-24 months after diagnosis and die of recurrent metastatic disease within 5 years, a subset survive more than 5 years even after their cancers recur. If we could find out why some patients with HGSOC survive much longer than others, we could develop more effective strategies to treat these patients with this subtype of ovarian cancer. The immune system plays an important role in modulating cancer growth and progression. Recently, we and other investigators found that patients with ovarian cancer survive much longer if their tumor tissues have more of a type of immune cell called CD8+ cytotoxic T cells (CTLs). It is known that high levels of CD8+ CTLs in tumor tissues are due to the stimulation of CD8+ cell proliferation, as well as an enhanced ability of CD8+ cells to travel from the bloodstream through the stromal tissues to cancer cells. However, the reasons why more CD8 + CTLs are activated in a subset of ovarian tumors than in others are not fully understood. In this application, we propose to identify novel mechanisms by which CD8+ CTL numbers in the tumor tissue are reduced in a subset of patients with HGSOCs. The project is based on the observations that expression levels of a protein called microfibrillar-associated protein 5 (MFAP5) in a subpopulation of cells in the tumor tissue called cancer-associated fibroblasts (CAFs) were associated with CD8+ CTL numbers in HGSOCs. We have demonstrated that MFAP5 itself is a marker associated with poor survival rates in patients with HGSOCs. MFAP5 can bind to a receptor called the alpha(v)-beta(3) integrin, which is essential for CD8+ CTLs to migrate from blood vessels through the cancer-supporting tissue known as the extracellular matrix and to ovarian cancer cells. Recently, we have shown that MFAP5 can kill CD8+ CTLs via a process called apoptosis and that MFAP5 can upregulate a protein called CD47, which is a known T cell suppressor, in both ovarian cancer cells and CD8+ T cells. CD47-producing cells generate a "don t eat me" signal that prevents immune cells called macrophages from engulfing them, which subsequently stops the macrophages from presenting molecules that activate CD8+ T cells. In the present application, we will determine how CAF-derived MFAP5 can suppress these immune responses in HGSOCs. To this end, we will use novel ovarian cancer mouse models, a novel gene delivery vehicle called exosomes, anti-MFAP5 antibodies, and state-of-the-art imaging technology to determine the effects of MFAP5 silencing and blockade on CD8+ CTL density in ovarian tumor tissue, ovarian cancer metastasis, and survival of ovarian cancer. We will also determine how CD47 mediates the effect of MFAP5 on suppressing CD8+ T cell activation and how MFAP5 inhibits CD8+ T cell motility in the extracellular matrix of the ovarian tumor tissue. Finally, we will determine the mechanism by which MFAP5 upregulates CD47 in ovarian cancer cells and CD8+ T cells. Recent advances in cancer treatment have led to great hope that immunotherapy, a technology that harnesses the power of the immune system to provide cell-based and antibody-based treatments for cancer, can be combined with other standard cancer treatment modalities such as surgery, chemotherapy, and biologic therapy. T
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710126
Entities
People
- Samuel C. Mok
Organizations
- United States Army
- University of Texas at Austin