The interference of gut bacteria could explain the ineffectiveness of immune checkpoint therapy in some patients with ovarian cancer, according to a recent study published by McGinty et al in Cancer Immunology Research.
Background
There are over 10,000 ovarian cancer–related deaths in the United States per year, making it one of the deadliest gynecologic cancers in the country. Despite improvements in the clinical management of the disease, survival rates have improved little during the past several decades.
Physicians treating patients with ovarian cancer were initially enthusiastic about the potential of immune checkpoint therapy—a type of immunotherapy that boosts the immune system’s ability to destroy cancer. However, they found that while immune checkpoint therapy has improved outcomes among patients with melanoma, urothelial carcinoma, and other types of cancers, ovarian cancer cells were resistant to treatment.
Previous research has demonstrated that an unhealthy gut microbiome could help 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,” explained senior study author Melanie Rutkowski, PhD, of the Department of Microbiology, Immunology, and Cancer Biology at the University of Virginia (UVA) Cancer Center. “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,” she emphasized.
Study Methods and Results
In the study, researchers examined flagella—the tiny hair-like, locomotive structures in bacteria made of a material called flagellin. They noted that flagellin may contribute to the lack of treatment response in patients with ovarian cancer treated with immune checkpoint therapy.
The researchers determined that in ovarian cancer, bacteria and the flagellin they contain cause chaotic cellular communications that prevent immune cells from finding their way into and around ovarian cancer cells, thereby disrupting the success of the immune checkpoint therapy.
“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,” Dr. Rutkowski noted. “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 [checkpoint] therapy,” she indicated.
With the discovery, the tumors’ defenses could result in new opportunities to target the cancer cells. In early lab tests, the researchers discovered that they could block the chaotic signaling caused by the flagellin to restore the effectiveness of immune checkpoint therapy.
“In mice whose immune cells … lack the ability to recognize flagellin, immune [checkpoint] therapy induced long-term control of ovarian tumor growth in almost 80% of animals,” Dr. Rutkowski highlighted. “That we observed this response using multiple aggressive ovarian cancer cell lines suggests that inhibiting this pathway has potential to enhance clinical outcomes [in patients with] ovarian cancer,” she continued.
Conclusions
The findings revealed how the gut microbiome is vital not only to maintain overall health but to enhance the efficacy of cancer therapy. The researchers hope to use the results of their study to improve cancer care among patients with ovarian cancer and many other types of cancers. Nonetheless, more research is needed to increase the efficacy of immune checkpoint therapy in this patient population.
“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 [checkpoint] therapy response for ovarian cancer specifically, which is an area we are actively investigating,” underscored Dr. Rutkowski. “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. [We are] 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 [patients with] ovarian cancer,” she concluded.
Disclosure: The research in this study was supported by the National Cancer Institute, with personnel support from the American Cancer Society, UVA Cancer Center, and UVA’s Beirne B. Carter Center for Immunology Research. For full disclosures of the study authors, visit aacrjournals.org.
