Researchers at UC Davis have received $3.2 million in federal funds to further investigate how obesity and inflammation affect the body’s immune system in fighting cancer.
The collaborative project brings together researchers from four UC Davis departments to better understand the mechanisms underlying the susceptibility of obese animal models to the toxicities associated with immunotherapy and to graft-versus-host disease, a complication of stem cell transplantation. The investigators also will examine the role of the microbiome in obesity and whether the diversity of gut bacteria plays a role in immune system function.
Immunotherapy is increasingly being used to help the body’s natural defenses kill cancer cells, and while there have been dramatic successes, the approach also can cause serious side effects for cancer patients. Graft-versus-host disease can occur in leukemia and lymphoma patients following a donor stem cell transplant (known as an allogeneic hematopoietic stem cell transplant). In this case, the donor immune system regards the recipient’s normal tissues as foreign and mounts an immune response, attacking the recipient’s tissues and organs. Understanding these mechanisms is essential to enhancing treatment effectiveness and improving patient outcomes.
The research is being led by William J. Murphy, professor in the UC Davis Departments of Dermatology and Internal Medicine. The other researchers are Mehrdad Abedi, a hematologist-oncologist with the UC Davis Comprehensive Cancer Center, Alice Tarantal, professor in the Departments of Pediatrics and Cell Biology and Human Anatomy, and the UC Davis Primate Center, and Dennis Hartigan-O’Connor, assistant professor in the Department of Medical Microbiology and Immunology and the Primate Center.
The current project expands on earlier UC Davis immunology research related to obesity and its profound effect on the immune system. In one study, Murphy’s team demonstrated that obese mice are more susceptible to immunotherapy’s toxicities than lean mice. More recently, they found that obese mice also succumb more quickly to graft-versus-host disease after receiving allogeneic stem cell transplants. In other work, Murphy’s team found that tumors grow faster in obese mice than they do in lean mice, and in an ongoing project with the UC Davis School of Veterinary Medicine, they are examining the impact of inflammation in obese dogs with spontaneous tumors on the chemotherapy and radiation treatment-related toxicities. They are also researching means to prevent this inflammation and toxicity.
“We have been doing comparative medicine research finding commonalities between the species and differences between the species,” Murphy said. “We realized that looking at larger, outbred animals like dogs or nonhuman primates will provide a critical link before applying this knowledge to humans.”
One question Murphy and his colleagues hope to answer in their new work is whether the microbiome (the bacteria of the gut) in primate, dog and mouse models contributes to obesity or whether it’s the other way around. Animals with high fat content tend to have less diverse gut bacteria, which can affect the immune system and promote inflammation.
The researchers also will use the obese nonhuman primate model to test stem cell transplants (both allogenic and autologous) to determine how the extra weight affects the animals’ immune system. In addition, they will look at the incidence of graft-versus-host disease in the animals, then testing to determine whether anti-inflammatory agents can block the inflammation and reduce the effects.
“With an aging population and an increase in rates of obesity, understanding the effects on the immune system is critical,” Murphy said. “By linking all four species (mouse, dog, nonhuman primate and humans) in one study we can see how obesity is changing the immune system and can affect disease progression as well as potential therapies. Using all of these models gives the most complete answers.”
The project is funded with an NIH grant No. R01CA214048.