Reversing Immunotherapy Resistance in Ovarian Cancer by Targeting a Novel Immune-Suppressive Factor Released by Tumor-Associated Macrophages (TAMs)
Abstract
Recurrent ovarian cancer continues to be among the most lethal forms of tumors in women, with estimates of over 21,000 new cases being diagnosed in 2015. Thus, the development of more effective treatments for ovarian cancer is urgently needed. While important progress has been made in new therapies for cancers, including immunotherapy, this important new treatment strategy has demonstrated only minimal effects when used to treat ovarian cancers. Thus, it is critical that we understand why such an effective treatment for other types of tumors has a minimal effect in ovarian cancer. This limited effect is surprising given the important role the immune system plays in ovarian cancer. To this end, our laboratory made the unexpected discovery that a small fragment of a common protein, called collagen, is generated and secreted by a group of supporting cells, termed macrophages. This recently discovered soluble peptide might have the unique ability to help make ovarian tumor cells invisible to the immune system by disrupting the ability of the body s natural immune cells to detect and destroy the tumor cells. In order to understand this unique soluble collagen fragment in more detail, we developed a highly specific antibody that selectively blocks the function of this peptide by preventing it from binding to immune cells and thereby blocking immune suppressive activity. Given our exciting preliminary studies, this proposal is designed to test whether targeting the recently identified collagen fragment will "reactivate" immune control of ovarian cancer and enhance the efficacy of the new class of immune checkpoint inhibitors by selectively disrupting a previously unknown signaling pathway. These studies will use a highly innovative and comprehensive set of in vitro and in vivo experimental approaches to establish the molecular and cellular mechanisms that may lead to a more effective treatment paradigm for ovarian cancer. These innovative new studies specifically address a number of the focus areas that represent the vision and mission of the Ovarian Cancer Research Program, including treatment resistance, optimizing immunotherapy, and understanding host-tumor interactions. When taken together, our proposed studies may accelerate translating these new findings into innovative approaches to unleash the full potential of immunotherapy for treating military personnel and others suffering from ovarian cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710099
Entities
People
- Peter C Brooks
Organizations
- Maine Medical Center
- United States Army