Exploiting the Immunometabolome to Enhance Antitumor Immunity in Ovarian Cancer
Posted December 3, 2021
Julian J. Lum, Ph.D., BC Cancer, part of the Provincial Health Services Authority
Marisa Kilgour, Ph.D Student and First Author
Phineas Hamilton, Ph.D., Research Associate and Co-Senior Author
Dr. Julian J. Lum
Dr. Phineas Hamilton
Traditionally ovarian cancer patients have been given three options for treatment: chemotherapy, radiation, and/or surgery1. Patients experience the best rate of survival when diagnosed early; however, only about 15 percent of all cases are diagnosed during the early stages2. Immunotherapy, a form of cancer treatment that utilizes the body’s immune system to prevent, control, and eliminate cancer, has been successfully implemented for other cancers, but only with limited effect for ovarian cancer patients. In general, ovarian tumors with more tumor infiltrating lymphocytes (TILs) that are endowed with potent antitumor phenotypes have a higher likelihood of improved overall survival rates. However, efforts to reinvigorate TIL with immunotherapy approaches have not been successful in this disease. It is clear that a significant gap remains in understanding why ovarian cancer patients have poor response rates to immunotherapies. With the support of an Ovarian Cancer Research Program (OCRP) FY17 Pilot Award, Dr. Lum focused on delineating the tumor T-cell metabolome to understand how metabolism can block effective immunotherapy.
The research team hypothesizes that T-cell intrinsic metabolic pathways that are activated in the tumor environment can be immune suppressive and this can be overcome by genetically rewiring these metabolic programs to enhance effectiveness of chimeric antigen receptor T-cells (CAR-T). Dr. Lum’s team decided to use advanced artificial intelligence (AI) tools to map the first metabolome in ovarian cancer. This AI approach also enabled them to infer which metabolites were used and present in the tumor environment. Dr. Lum identified a metabolite known as 1-methylnicotinamide (1-MNA) that can turn off CAR-T, a type of gene-engineered immune cell used in immunotherapy. Dr. Lum’s group found that 1-MNA is produced by the surrounding cancer cells and cancer-associated cells, implying that ovarian cancer cells produce 1-MNA to shut off the cancer-fighting function of the immune system.
Bioinformatics and flow cytometry-based results found that the TILs and cancer cells have different metabolic profiles compared to T-cells. The ovarian cancer cells’ metabolic profiles reflect more glycolytic and oxidative activity as compared to T-cells. Dr. Lum completed metabolic profiling analysis to clarify the metabolic phenotype of each cell type. The metabolite profiling analysis revealed that from all the metabolites analyzed, 1-MNA was the most differentially abundant metabolite in T-cells and tumors in the ascites (the buildup of fluid in the space around the organs in the abdomen). In addition, 1-MNA was higher in T-cells located within the tumor compared to T-cells in the ascites.
Dr. Lum showed that the tumor microenvironment can influence T-cell metabolism, and that metabolites may contribute indirectly to promoting tumor development as well as suppressing the human immune response. The results revealed immune metabolome differences between cells in the tumor and ascites of patients. Future research will focus on ways to make CAR-T cells resistant to 1-MNA using CRISPR-Cas9 gene-editing technology and strategies to prevent 1-MNA and other immunomodulatory metabolites from inhibiting immunity against ovarian cancer. With the breakthrough discovery of a metabolic contribution to the tumor microenvironment and its interaction with the anti-cancer responsibilities of T-cells, Dr. Julian Lum hopes to provide insight to why only a portion of the patients respond to immunotherapy treatment, enabling a more targeted approach to treatment for ovarian cancer patients.
Last updated Thursday, May 26, 2022