MUSC Hollings Cancer Center researchers received a grant from the Department of Defense to investigate how dietary fat affects the development of colon cancer and to find more effective methods of treatment.
Raymond N. DuBois, M.D., Ph.D., director of Hollings Cancer Center and lead investigator, said this is part of the DOD’s peer-reviewed cancer research program (PRCRP) Idea award. One of the goals of this program is to increase mission readiness and quality of life by decreasing the burden of cancer on service members and their families, veterans and the American public.
Colorectal cancer is the third most common malignancy and second leading cause of cancer-related death in the United States. Among U.S. veterans, colorectal cancer is the second most common type of cancer. A high-fat diet is a risk factor for developing obesity, cardiovascular disease and diabetes. Obesity is associated with increased risks of various cancers, including colorectal cancer.
Being overweight significantly affects the health and readiness of U.S. military personnel and the health of their families, especially in recent decades. The percentage of obese military personnel increased from 5% in 1995 to nearly 15% in 2015. “Exactly how dietary fat intake contributes to colorectal cancer remains elusive. It is also unknown whether dietary fats suppress a host’s immune response against tumor cells,” said DuBois.
The proposed research will address these challenging questions and discover potential new targets for treatment and/or prevention of colorectal cancer, DuBois said. “Because early clinical symptoms do not always occur in a reliable fashion in people at risk for colorectal cancer, the diagnosis and treatment can be delayed. More often than not, patients present with late-stage colorectal cancer, for which existing therapies have limited efficacy.”
The human immune response is regulated by a balance between co-stimulatory and inhibitory (checkpoint) pathways. “Immune checkpoints put brakes on the immune system so that it stays in balance, which prevents inflammatory tissue damage and autoimmune diseases,” he said.
“Immune checkpoint pathways are activated by interaction of immune checkpoint receptors such as PD-1 with its ligand PD-L1. Ideally, our immune system must kill tumor cells; however, tumor cells can hijack immune checkpoint pathways to shut down the immune response under certain conditions,” said DuBois.
The DOD grant will allow DuBois’ team to investigate whether dietary fats suppress hosts’ immune responses against tumor cells via immune checkpoint pathways. The team recently published a study in Oncogene, which showed for the first time how a checkpoint inhibitor is regulated through a tumor suppressor gene that affects colorectal cancer.
Tumor immune evasion: A cloaking device
Nuclear hormone receptors are a class of proteins found within cells that are responsible for sensing certain biomolecules. “One nuclear hormone receptor, peroxisome proliferator-activated receptor delta (PPARd), plays a central role in regulating the storage and metabolism of fatty acids. Although there is a known connection between PPARd and colorectal cancer, the connection needs further clarification,” said DuBois. This is especially true with respect to how PPARd allows tumors to evade immune attack and continue growing, which DuBois described as being much like a cloaking device.
DuBois’ team collected preliminary data that indicated the activation of PPARd makes tumor cells invisible to the immune system. “Because certain fatty acids can activate PPARd, we postulate that dietary fats induce tumor immune evasion, and PPARd is one of the mediators of these effects,” said DuBois.
The results from this line of inquiry will not only establish a previously unrecognized role of PPARd in affecting tumor immune evasion but also a potential mechanism underlying the contribution of dietary fat to colorectal cancer. “For long-term studies, our findings will provide a rationale for developing effective drugs that act as PPARd antagonists and target immune checkpoint pathways for use in patients with colorectal cancer,” said DuBois.
“We are evaluating drugs that could target this nuclear receptor (PPARd) and inhibit it,” said DuBois. “We will need to examine whether inhibiting this pathway is effective – especially because this hasn’t been examined in this context.”
There are other pro-inflammatory pathways, apart from the checkpoint inhibitor pathway, that inhibit the immune system’s ability to attack tumors. “We are examining those in addition to checkpoint inhibitors, and in preliminary animal studies, they appear to be more effective and could result in an efficient combination therapy for colorectal cancer,” said DuBois.
“Our team is trying hard to understand why colon cancers in general do not respond well to immunotherapy, and this research may stimulate other groups to attack this problem in several different ways,” said DuBois.