University of Virginia Cancer Center researchers have explained the failure of immune checkpoint therapy for ovarian cancer by discovering how gut bacteria interfere with the treatment. Doctors may be able to use the findings to overcome this treatment failure and save the lives of thousands of women every year.
The new discovery, from the lab of UVA's Melanie Rutkowski, PhD, speaks to the surprising ways that the microbiome – the collection of organisms that live on and inside our bodies – is vital not only to maintain health but for the effectiveness of medical treatments.
As a leading microbiome researcher, Rutkowski is excited about the potential of her field to improve care not just for ovarian cancer but for many other cancers. She has already shown, for example, how an unhealthy gut microbiome helps breast cancer spread . "As soon as we are born, the gut microbiome is critical for educating our immune system so that diseases are controlled and that we are not damaged in the process by an over exuberant immune response," she said. "We and others are discovering the far-reaching impact that microbiome/immune cell interactions have on almost every aspect of our being, from influencing metabolic health, organ health and even the relationship between the gut and the brain. This is why it is critically important to understand how the relationship between our microbiome and immune system changes during a disease like cancer, as this research could uncover novel therapies capable of helping the immune system kill cancer cells."
Targeting Ovarian Cancer
Ovarian cancer kills more than 10,000 American women every year, making it the deadliest gynecological malignancy in the United States. Despite improvements in the clinical management of the disease, survival has improved very little during the past several decades. Doctors treating patients with ovarian cancer had been excited about the potential of immune checkpoint therapy – a form of immunotherapy that enhances the immune system's ability to destroy cancer – only to find that the ovarian tumors were stubbornly resistant. This treatment approach is improving outcomes for patients with melanoma, bladder cancer and other cancers, so what is different about ovarian cancer?
Rutkowski and her team have finally found answers, and they found them in the tiny propellers bacteria use to move. These propellers, called flagella, are hairlike structures made of a material called flagellin. It is flagellin, the researchers found, that is the key to why immune checkpoint therapy does not help ovarian cancer patients as it does for patients with other types of cancer.
In ovarian cancer, Rutkowski and her team determined, bacteria and the flagellin they contain disrupt the success of the immune checkpoint treatment. The flagellin causes chaotic cellular communications that prevent immune cells from finding their way into and around the ovarian tumors. "We found that ovarian tumors enhance the ability of flagellin from the gut to get into the tumor environment, where they normally should not be," Rutkowski said. "Because of the gut leakage, immune cells that recognize flagellin become reprogrammed to support tumor growth instead of supporting the killing of tumors during immune therapy."
With the discovery, the tumors' defenses could become their Achilles' heel. The researchers found that, in early lab tests, they could block the chaotic signaling caused by the flagellin to restore the effectiveness of immune checkpoint therapy. "In mice whose immune cells that lack the ability to recognize flagellin, immune therapy induced long-term control of ovarian tumor growth in almost 80% of animals," Rutkowski said. "That we observed this response using multiple aggressive ovarian cancer cell lines suggests that inhibiting this pathway has potential to enhance clinical outcomes for ovarian cancer patients."
While much more research will need to be done, Rutkowski's findings suggest we may yet have a way to turn immune checkpoint therapy into a powerful tool against ovarian cancer and, ultimately, save lives.
"The idea that immune cell recognition of bacterial flagellin leads to the failure of immune therapy is somewhat opposite to what is known about how this pathway influences immune cell behavior. We believe that there is a unique reason why flagellin inhibits immune therapy response for ovarian cancer specifically, which is an area we are actively investigating," said Rutkowski, of UVA's Department of Microbiology, Immunology and Cancer Biology. "The survival outcomes we are achieving in mice that lack the ability to recognize flagellin are extraordinary, especially if we manage to translate these observations into the clinic. I am very hopeful that this work will help to establish a dialogue about the potential that inhibiting the ability of immune cells to recognize bacterial flagellin may have for ovarian cancer patients."
Rutkowski's cutting-edge ovarian cancer research is part of UVA's sweeping effort, called the TransUniversity Microbiome Initiative, to better understand and harness the microbiome to improve human health.
Findings Published
The researchers have published their findings in Cancer Immunology Research . The research team consisted of Mitchell T. McGinty, Audrey M. Putelo, Sree H. Kolli, Tzu-Yu Feng, Madison R. Dietl, Cara N. Hatzinger, Simona Bajgai, Mika K. Poblete, Francesca N. Azar, Anwaruddin Mohammad, Pankaj Kumar and Rutkowski. The scientists have no financial interest in the work.
The research was supported by the National Cancer Institute, grant R01CA253285, with personnel support from the American Cancer Society, UVA Cancer Center and UVA's Beirne B. Carter Center for Immunology Research.
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