Gut microbiome attack cancer cells by enhancing immune cells: study
Patients with gastric cancer have been shown to have a reduced gut microbiome, which has antitumor effects.
Accordingly, amid the brisk attempts to use new immune-oncology treatments for advanced or recurrent gastric cancer patients, it was found that using gut microbiome to enhance the function of immune cells gathering around cancer can effectively kill cancer cells.
A research team from the Catholic University of Korea College of Medicine analyzed the functional gut microbiome and immune cells of gastric cancer patients and found that butyrate, a beneficial metabolite of the gut microbiome reduced in gastric cancer patients, controls the immune decline in the tumor microenvironment.
The research team was led by Professor Song Kyo-young (co-corresponding author) of the Department of Gastroenterology at Seoul St. Mary Hospital, Professor Jung Yoon-ju (co-author) at Yeouido St. Mary’s Hospital, Professor Cho Mi-la (co-corresponding author) and researcher Lee Seung-yun (first author) of the Intermediary Immunology Laboratory in the Department of Biomedical Sciences.
Butyrate is a metabolite of fecal bacterium, a type of short-chain fatty acid (SCFA) produced during the breakdown and fermentation of fiber. It is known to have beneficial functions, including reducing inflammation of the colon's mucosal lining, boosting the immune system, and aiding in the digestive process. It is unclear why the amount of butyrate-producing bacteria varies from person to person. Still, it is believed that the composition of the gut bacteria may increase the risk of developing severe infectious disease.
Given that the gut microbiome regulates the function of immune cells, the researchers noted its association with response to recent immune checkpoint inhibitor treatments, such as anti-PD-1/anti-PD-L1 immuno-oncology drugs. To investigate the association between the gut microbiome and immunocompromised status in gastric cancer patients, they analyzed immune cell subtypes in gastric cancer patients' blood and tumor tissue.
The results showed that patients with advanced gastric cancer had higher expression of PD-L1 and IL-10, known as immunosuppressive factors, in their blood and tumor tissue than patients with early gastric cancer.
They also analyzed the gut flora of gastric cancer patients and found that some butyrate-producing gut bacteria were reduced. The reduced strains included faecalibacterium, collinsella, which activates the immune response, and bifidobacterium, which aids digestion.
To determine how butyrate, a metabolite secreted by the gut flora, affects gastric cancer cells, the team used a gastric cancer avatar model (mice transplanted with immune cells from gastric cancer patients).
The results showed that butyrate inhibited the expression of PD-L1 and IL-10 in gastric cancer cells in an in vivo model, demonstrating its antitumor effects by inhibiting cancer promotion. While the antitumor effects of butyrate have been studied, it was the first time that specific effects have been confirmed in a gastric cancer model.
Gastric cancer has a high cure rate when detected early. Still, patients with advanced or recurrent gastric cancer have a poor prognosis, and a new treatment, immuno-oncology, is being tried. Unlike cytotoxic or targeted therapies that act directly on the tumor, immuno-oncology is less toxic because it induces an immune response from the patient's immune system to produce an antitumor effect.
The most well-known immuno-oncology drugs are immune checkpoint inhibitors, which inhibit the immune checkpoint protein (PD-L1 protein) activity to induce the body's T cells to attack tumor cells. However, gastric cancer has not shown promising results compared to other tumors because it is difficult to expect an immunological response in the tumor's microenvironment.
“It is very important to understand the immune status of patients during the development of cancer and at the time of recurrence, and research has led to the development of immunotherapy drugs in the clinic,” Professor Song said. “This is a very important study that confirms the possibility that the gut flora may play an important role in overcoming the immunosuppressed state, as factors to select patients for whom immunotherapy can be expected to be effective and to enhance treatment response are still lacking.”
Professor Cho said, “This study confirms that the composition of the gut flora and associated metabolome of gastric cancer patients may be an important target for immune checkpoint inhibitor therapy in gastric cancer.”
She continued, “The development and study of a patient-mimicking avatar model that reflects the immune cellular status of patients is significant, and the confirmation of immunosuppressive functions in a humanized gastric cancer mouse model, as well as in a mouse model of pre-neuronal degeneration and liver transplantation, may have future applications in the treatment of various cancer diseases.”