Reversing Immunotherapy Resistance in Ovarian Cancer by Targeting a Novel Immune-Suppressive Factor Released by Tumor-Associated Macrophages (TAMs)
Abstract
Ovarian cancer remains a major health problem for women globally. While progress in developing new treatments strategies including immunotherapy for some types of cancer has been made, these approaches have had only limited impact in ovarian cancer. To this end, the current proposal was designed to test the central hypothesis that targeting the soluble RGDKGE collagen fragment may re-activate immune control of ovarian cancer and enhance the efficacy of immune checkpoint inhibitors by selectively disrupting a novel integrin-dependent signaling cascade. Our data suggest for the first time that ID8-VEGF andSKOV-3 tumors can generate the low molecular weight RGDKGE-containing collagen fragment that binds to the cell surface integrin alpha-V-beta-3. Cellular interactions with the RGDKGE-containing collagen fragment may lead to a unique signaling cascade that regulates YAP nuclear localization and may also control the expression of immune checkpoint molecules in selected immune cell lines. Selective targeting of the RGDKGE-containing collagen fragment inhibited ovarian tumor growth in murine models. Collectively, these observations provide new mechanistic insight into how an endogenously generated soluble collagen fragment may regulate ovarian tumor growth and may help with the development of alternative strategies to manage ovarian cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2020
- Accession Number
- AD1115894
Entities
People
- Peter C Brooks