A team of researchers at the University of Chicago has discovered that certain commensal bacteria may promote the development of murine leukemia virus (MuLV) leukemia in mice, by suppressing the adaptive anti-tumor immune response.
The research showed that when both the virus and the commensal bacteria are present in mice, three negative immune-regulating genes are upregulated, which in turn dampen the immune response that would otherwise kill cancer cells. Two out of three negative immune regulators are known to be indicators of poor prognosis for humans with some forms of cancer.
“These two negative immune regulators have been well documented as poor prognostic factors in some human cancers, but no one knows why,” said Tatiana Golovkina, PhD, professor of microbiology at the University of Chicago. “Using a mouse model of leukemia, we found that the bacteria contribute to the regulation of these negative immune regulators, allowing the developing tumors to escape recognition by the immune system.”
Golovkina is lead author of the study published by the team at cell reportswhich bears the title,The commensal gut bacteria enhance the pathogenesis of retrovirus in cancerous miceIn which they concluded, “This work describes the mechanism by which bacteria promote tumor formation within distant organs in the intestine and direct potential targets for cancer therapy.” “
Gut bacteria have a profound impact on health by aiding digestion, providing nutrients and metabolites, and working with the immune system to ward off pathogens. “Importantly, microbiota is among the factors that influence the development of tumors,” the authors wrote. “Intestinal microbes are implicated in the development of cancers of the intestine and associated organs.”
Cancer is usually thought to be caused by spontaneous mutations that cause cells to grow and multiply out of control, forming tumors. In 1910, pathologist Peyton Ross took a sample of a cancerous tumor in a chicken and injected it into a healthy bird, which then also developed cancer. Its discovery was denied at the time, but researchers later discovered that the cancer is transmitted by retroviruses. This discovery prompted further research and subsequent identification of several retroviruses that cause different types of cancer.
Some cancer-causing retroviruses take advantage of the gut microbes to proliferate and multiply. for example, In a 2011 studyGolovkina and her team found that the virus that causes breast tumors in mice depends on gut bacteria, enabling the virus to block immune responses from recognizing and eliminating infected cells. Thus, microbes help the virus to reproduce and as a result, tumors develop. “Some carcinogenic retroviruses take advantage of germs to spread and multiply,” the team continued. “Previously, we have shown that transmission of murine breast tumor virus (MMTV), which causes breast cancer in susceptible mice via destructive mutations, is dependent on commensal gut bacteria.”
The researchers wanted to find out whether the commensal bacteria influence the development of cancer caused by the virus in a way other than by aiding its reproduction. The scientists commented, “The ability of germs to regulate viral replication and pathogenesis due to viruses belonging to different families, our interest in its impact on MuLV-driven pathology has begun,” the scientists commented.
In their study, they used germ-free (GF) mice that do not have gut microbes, and specific pathogen-free (SPF) mice that do not have any pathogenic microbes that can cause disease, but have common microbes, including bacteria. that naturally fills the alimentary canal. Both GF and SPF mice were infected with murine leukemia virus. While the virus infected and spreads well in both types of mice, only the SPF-infected mice developed high-frequency tumors.
All virus-induced tumor cells display viral antigens, or molecules that mark them as foreign to the host and make them targets for immune attack. In order for virus-induced cancer cells to continue reproducing, they must be protected from immune system attack, therefore, Golovkina’s team searched for a microbial-dependent immune evasion mechanism that enables virus-induced cancer cells to survive in the host.
The team conducted a series of experiments on immunocompromised mice that were designed to lack an adaptive immune system. In a germ-free environment, these mice developed tumors when exposed to the virus at the same frequency as immunocompetent SPF mice with healthy immune systems. Therefore, the anti-tumor immune response was abolished by the microorganisms, which were subsequently identified as commensal bacteria. “In our study of retroviral leukemia that originates in an organ distant from the intestine, we found that commensal intestinal bacteria promote leukemia formation,” they wrote.
The researchers then found that the commensal bacteria induced three genes known as passive immune regulators in infected mice. These genes normally turn off the immune system after it has dealt with a pathogen, but in this case, it impedes an immune response directed against cancer cells. Two of three negatively regulated immune regulators – Serpinb9b and Rnf128 – are also known to be indicators of poor prognosis in humans with some spontaneous cancers.
The team stated that “the promotion of leukemia development by symbiosis is due to the suppression of the adaptive immune response through the regulation of several immune-negative regulators.” These include negative regulators serpinb9b and Rnf128, which are associated with a poor prognosis of some human spontaneous carcinomas.
Not all commensal bacteria have tumor-stimulating properties, so Golovkina and her team continue to investigate further why this ability to suppress immunity is only present when both viruses and bacteria are present. “Now we have to understand what characterizes bacteria that have these characteristics,” she said.
The authors further commented in their paper, “…for the first time, we demonstrate that commensal bacteria facilitate the development of leukemia through the induction of negative regulators of the immune response – a novel mechanism mediated by the gut microbiota that enables tumor progression … because these negative regulators can be Because of the poor prognosis in some human cancers, it is likely that similar mechanisms of immune evasion may operate in tumors caused by viruses and possibly in spontaneous tumors of non-viral origin.”