Dr. Curtis' research in her Immunometabolism and Cancer Immunology Lab at Mayo Clinic is focused on immunometabolism, cancer immunotherapy and tumor antigens in ovarian cancer.
Immunotherapy is delivering unprecedented success in many cancer types. However, responses to these agents, particularly checkpoint inhibitors, have been disappointing in people with high-grade serous ovarian cancer (HGSOC). One possible explanation for this may be the unique tumor microenvironment at the site of metastasis. The tumor microenvironment could alter metabolic pathways and provide unique metabolic substrates, changing the function of immune cells.
Metabolic reprogramming has been shown to control immune cell function and differentiation in many settings, including cancer. Metastatic HGSOC tumors are composed of cancer cells and stromal cells including adipocytes, fibroblasts, macrophages, T cells and B cells, but little is known about how the immune cell landscape shifts during metastasis and how the interactions between the stromal cell types may influence immune function during tumor progression. Dr. Curtis and her research team are working to determine whether adipocytes and fibroblasts in the omentum modulate the function of immune cells during metastasis through metabolic reprogramming.
Immunotherapies that instruct the immune system to specifically target tumors have recently been discovered. Development of effective blocking antibodies against immune checkpoint receptors and their ligands has led to an explosion of clinical testing in many cancer types.
Some people treated with checkpoint inhibitors experience durable remissions. However, despite promising clinical results, checkpoint blockade therapies are successful in only a subset of patients, and specific tumor types, such as high-grade serous ovarian cancer (HGSOC), do not respond favorably.
This may be due to a relatively low mutation burden present in their tumors, which corresponds to low numbers of neoantigens, therefore, HGSOC is often thought of as a nonimmunogenic cancer.
Nevertheless, research has shown a positive association between increased numbers of infiltrating T cells and prolonged survival of people with HGSOC and that clinically relevant tumor antigens do exist in HGSOC. Together, these studies demonstrate that the immune system has a strong involvement in the biology of HGSOC and that patients could benefit from new immunotherapeutic strategies.
The lab's goal is to develop new immunotherapy treatment strategies that improve therapeutic outcomes for people with advanced-stage ovarian cancer. This is accomplished using immunopeptidomics to identify personalized tumor antigens that improve the immunogenicity of dendritic cell vaccines.
A patient-specific immunopeptidome will lead to the identification of immunogenic tumor antigens that bind major histocompatibility complex receptors on dendritic cells and activate T cell responses specific to each person's tumor. Elucidating the immunopeptidomic landscape of an individual's tumor will allow the lab to generate a multiantigen vaccine tailored to his or her cancer and may improve the therapeutic response to dendritic cell vaccines.
Dr. Curtis' research team expects to identify new tumor-associated antigens from primary ovarian tumors and validate the immunogenicity of a personalized dendritic cell vaccine strategy that can be tested and validated in the future.