A new study by researchers from the University of Chicago has found that some commensal bacteria may promote the development of leukemia caused by the murine leukemia virus (MuLV) in mice, by suppressing the adaptive anti-tumor immune response. The team’s research showed that when both the virus and commensal bacteria are present in mice, three negative immune regulator genes are upregulated, which in turn tamps down the immune response that would otherwise kill the tumor cells. Two of the 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 really well documented to be poor prognostic factors in some human cancers, but nobody knew why,” said Tatyana Golovkina, PhD, professor of microbiology at UChicago. “Using a mouse model of leukemia, we found that the bacteria contribute to upregulation of these negative immune regulators, allowing developing tumors to escape recognition by the immune system.”

Golovkina is senior author of the team’s published study in Cell Reports, which is titled, “Gut commensal bacteria enhance pathogenesis of a tumorigenic murine retrovirus,” in which they concluded, “This work describes a mechanism by which the microbiota enhances tumorigenesis within gut distant organs and points at 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 fend off pathogens. “Importantly, microbiota is among the factors influencing development of tumors,” the authors wrote. “The gut microbiota has been implicated in progression of cancers of the gut and associated organs.”

Cancer is usually thought to be the result of spontaneous mutations that cause cells to grow and multiply out of control, forming tumors. In 1910, pathologist Peyton Rous took a sample from a cancerous tumor in a chicken and injected it into a healthy bird, which then also developed cancer. His discovery was dismissed at the time, but researchers later discovered that the cancer was transmitted by a retrovirus. This discovery prompted more research and subsequent identification of numerous retroviruses causing various types of cancer.

Some cancer-causing retroviruses take advantage of gut microbes to spread and replicate. For example, in a 2011 study, Golovkina and her team found that a virus that causes mammary tumors in mice depends on gut bacteria, enabling the virus to block the immune responses from recognizing and eliminating infected cells. Thus, the microbes help the virus replicate and as a result, tumors develop. “Some oncogenic retroviruses take advantage of the microbiota for their spread and replication,” the team continued. “Previously, we demonstrated that transmission of mouse mammary tumor virus (MMTV), which causes mammary carcinomas in susceptible mice via insertional mutagenesis, depends on the gut commensal bacteria.”

The researchers wanted to see if commensal bacteria affected the development of a virus-induced cancer in a way other than assisting its replication. “The ability of the microbiota to regulate viral replication and pathogenesis caused by viruses belonging to different families initiated our interest in its influence on MuLV-driven pathology,” the scientists commented.

For their study, they used germ-free (GF) mice that had no gut microbes, and specific pathogen free (SPF) mice that don’t have any pathogenic microbes that could cause disease, but which do have common commensal microbes, including bacteria that normally populate the gut. The GF and SPF mice were both infected with the murine leukemia virus. While the virus infected and replicated equally well in both types of mice, only SPF mice developed high-frequency tumors.

Virally-induced cancer cells all express viral antigens, or molecules that mark them as foreign to the host and make them the targets for the immune attack.  For the virally-induced tumor cells to continue to replicate, they must be protected from the immune system’s attack, so, Golovkina’s team searched for a microbe-dependent immune evasion mechanism that enabled virally induced cancer cells to survive in the host.

The team performed a series of experiments with immunodeficient mice that were engineered to lack the adaptive immune system. In the germ-free setting, these mice developed tumors when exposed to the virus with the same frequency as immunosufficient SPF mice with intact immune systems. So, the anti-tumor immune response was being counteracted by microorganisms, which were subsequently identified as commensal bacteria. “In our studies of retrovirally induced leukemia that originates in an organ distant from the gut, we found that the intestinal commensal bacteria enhanced the leukemogenesis,” they wrote.

The researchers then found that commensal bacteria induced three genes known as negative immune regulators in infected mice. These genes normally act to shut down the immune system after it has dealt with a pathogen, but in this case, they held back an immune response directed against cancer cells. Two of the three upregulated negative immune regulators—Serpinb9b and Rnf128—are also known to be indicators of poor prognosis for humans with some spontaneous cancers.

“The promotion of leukemia development by commensals is due to suppression of the adaptive immune response through upregulation of several negative regulators of immunity,” the team stated. “These negative regulators include Serpinb9b and Rnf128, which are associated with a poor prognosis of some spontaneous human cancers.

Not all commensal bacteria had tumor-promoting properties, so Golovkina and her team are continuing to research more on why this immune-suppressing capability only comes into play when both virus and bacteria are present. “Now we have to figure out what’s so special about bacteria which have these properties,” she said.

The authors further commented in their paper, “… for the first time, we demonstrate that commensal bacteria facilitate leukemia development via induction negative regulators of the immune response—a novel gut microbiota-mediated mechanism that enables tumor progression … As these negative regulators can be linked to a poor prognosis in certain human cancers, it is likely that similar mechanisms of immune evasion operate in tumors induced by viruses and potentially in spontaneous tumors of non-viral origin.”

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