Mechanisms and Therapeutic Strategies for Overcoming MNA-Mediated Immune Suppression in Ovarian Cancer
Abstract
Summary of the Central Problem to Be Addressed: The excitement and promise of immunotherapy, a type of treatment that harnesses the immune system to fight cancer, has delivered life-saving treatments to many cancer patients. This success has caught the attention of biopharmaceutical companies who are pouring billions of dollars into research and development, acquisitions, and marketing to strengthen their immune oncology portfolios. However, ovarian cancer stands as an outlier because the current immunotherapies have not had any meaningful impact on patient outcomes. Naturally, the most pressing question is why are ovarian cancers refractory to immunotherapy and how do we override this resistance? To answer this crucial question, we need to consider what factors are present in the ovarian cancer environment that are blocking the cancer fighting properties of the immune system. Nutrient Metabolism – More Than a Recipe for Tumor Cell Growth and Division: Over the past decade, my laboratory and others have been studying the basic biology of ovarian cancer cell growth. Initially, we focused on how ovarian tumors acquire and process nutrients from the environment because the synthesis of building blocks is an absolute requirement for growth and function of a cancer cell. Yet, this work brought to light many unexpected insights. First, ovarian cancer cells consume large quantities of glucose, glutamine and other nutrients. Second, we learned that as a direct result of consuming large amounts of nutrients for cell division, tumor cells also secrete metabolic by-products such as lactate. Recent studies show that lactate and other secreted metabolites are not inert but rather they possess immune suppressive properties. Immunosuppressive Metabolites - Another Kind of Immunotherapy Firewall? New work from our laboratory and several others demonstrate that different cells found within tumors use metabolic by-products as a way to cripple the immune system. Such a strategy is similar to a warplane deploying flares to throw off laser-guided missiles. Collectively, these metabolites, while generally considered by-products, can profoundly change the landscape and alter the function of cancer fighting immune cells such as T cells. In addition, immunosuppressive metabolites can disable conductors of the immune system, namely macrophages and dendritic cells. These cells provide instruction to enable T cells to perform their cancer fighting properties. Therefore, it is becoming clear that metabolites serve a role beyond just feeding cells, and in fact act as a firewall preventing proper activation of antitumor immunity. One study in particular demonstrated that neutralization of methylglyoxal, a by-product of glucose metabolism, could improve the effectiveness of immune checkpoint inhibitors. This new research strongly suggests that blocking the action of immunosuppressive metabolites may be a potentially new avenue to restore the anti- cancer function of immune cells towards more effective immunotherapy for human ovarian cancer. Rationale and Objectives: In spite of the exciting work described above, many challenges and questions remain unanswered. With a few notable exceptions, the vast majority of investigations on cancer metabolism have been conducted on human tumor cell lines grown in petri dishes or from cancer cells harvested from mouse tumors. While these studies have been informative and provide a basis for further work, we are not aware of any publications examining immunosuppressive metabolites from human cancer tissues - a gap that is particularly glaring for ovarian cancer. With the original OCRP Pilot Award, our group to perform the first comparative metabolomic analysis of human ovarian tumors and T cells. Most relevant to the current Teal Expansion proposal was the identification of methylnicotinamide (MNA), a metabolite that was highly abundant in T cells which had infiltrated into primary tumors o
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210600
Entities
People
- Julian J. Lum
Organizations
- Provincial Health Services Authority
- United States Army