Despite thousands of studies, the role obesity plays in cancer risk and outcomes is still not fully understood. Obesity is generally associated with poor survival in cancer patients. Yet it appears to improve the effects of new class of immunotherapy drugs in a number of cancer types, including melanoma, ovarian, and certain lung and kidney cancers. New findings from a UTHSC research team published in the June issue of Cell Reports provide some exciting clues that breast cancer patients can hope for the same results.
Immune checkpoint blockade is a new class of cancer therapy, groundbreaking in improving patient outcomes for some cancers in the past decade, but it does not work for all cancers or all patients. Additionally, cancers are able to resist this type of immunotherapy via either immunosuppression or immune exclusion. Finding ways to retrain immune cells to recognize cancer is an active area of research at UTHSC.
Dr. Liza Makowski, professor in the Department of Medicine and the Center for Cancer Research, has long been interested in how the immune system is altered by obesity and how this impacts cancer risk and treatment. “Obesity is complex because it can cause both inflammation and activate counter inflammation pathways leading to immunosuppression. How obesity impacts cancer treatments is understudied,” said Dr. Makowski. Her lab teamed with Dr. Joe Pierre, assistant professor in Pediatrics and director of the UTHSC Center for Gnotobiotics, to investigate how obesity impacts immunotherapy and to identify potential biomarkers for successfully treating breast cancer patients.
The team’s lab findings showed immune checkpoint blockade could successfully curtail obesity-driven cancer progression in animal models. Anti-PD-1, an anti-cancer checkpoint inhibitor, increased immune cell numbers and markers of anti-tumor “aggression”. The team discovered tumor presence exacerbated an environment allowing tumors to hide, resulting in high levels of immunosuppressive cells that were ineffective to reduce breast cancer. Fortunately, these “sleepy cells” could be reprogrammed to reinvigorate anti-tumor immunity with anti-PD-1 despite persistent obesity. The group also worked to identify changes in the gut microbiome associated with obesity and a strong response to therapy. “Our gut is colonized by microbes including bacteria, fungi, and viruses, that may fundamentally impact our immune cells and our inherent ability to fight cancer in ways that we are only just beginning to understand,” said Dr. Pierre.
The Makowski and Pierre labs are currently funded by the National Cancer Institute to further investigate why certain microbes may impact cancer therapies.
Additional UTHSC investigators on the research team are: Tony N. Marion, PhD, professor in the Department of Microbiology, Immunology & Biochemistry; Hyo Young Choi, PhD, Department of Preventive Medicine; Neil Hayes, MD, MPH, professor of medicine, director of the UTHSC Center for Cancer Research, and division chief of Hematology and Oncology; and Ramesh Narayanan, PhD, professor in the Department of Medicine and the Division of Hematology and Oncology.
Congratulations to Drs. Makowski and Pierre! Read the article in Cell Reports here.