Immunotherapy has changed the way physicians treat cancer patients. This approach to therapy targets the immune system to redirect cells toward the tumor. Once a tumor is established and begins to proliferate, it secretes different proteins and molecules to polarize immune cells. This polarization turns immune cells from having an anti-tumor function to a pro-tumor function. Ironically, these very cells then help promote tumor growth and progression.
A way to combat pro-tumor polarized immune cells is to target key mechanisms in the tumor’s environment. One classic example of immunotherapy that takes advantage of a pro-tumor mechanism is immune checkpoint inhibitors (ICI). This treatment approach was first suggested a few decades ago and now has become standard-of-care in treatment regimens for select cancer types. In fact, this treatment has significantly improved the lives of many cancer patients. As a result, Drs. Tasuku Honjo and James Allison were awarded the Nobel Prize in Physiology or Medicine in 2018 for their pioneering work with ICIs.
Immune checkpoint inhibitors are designed to block specific surface makers on the cancer cell to avoid binding to the immune cell. Normally, this interaction would initiate a “do not eat me” signal to the immune cell. In our bodies this mechanism helps avoid immune cells from attacking healthy cells. However, cancer uses this process to protect itself from being recognized. It expresses the ligand that binds to an immune cell, known as T cells, and makes the body think it is not harmful. Once that interaction is blocked, T cells then can recognize the tumor and stop its progression and growth. Unfortunately, as a single agent, ICIs do not show great promise in the clinic. In many cancers in which it is available as treatment, ICIs are paired with chemotherapy or surgery. Therapeutic efficacy of ICIs is also limited based on tumor type and stage. Specifically, ICIs have little effect on ovarian cancer outcomes. Many scientists are working to try and improve therapeutic output in these cancer types.
A recent paper in Cancer Immunology Research, by Dr. Melanie Rutkowski and others, demonstrated that the collection of microorganisms in our bodies can affect ICI treatment outcomes in ovarian cancer patients. Rutkowski is an Associate Professor in the Department of Microbiology, Immunology, and Cancer Biology at the University of Virginia. Her work primarily focuses on the influence of microbes and bacteria on the immune system within cancer.
Rutkowski and her team established that in ovarian cancer bacteria and their flagellin can disrupt ICIs. Flagellin is a protein that helps bacteria move. Researchers found that it causes cellular chaos that prevents the immune cells from finding their way to the cancer. To confirm their findings, they treated mice whose immune systems lacked the recognition of flagellin with ICI. Rutkowski and others found that these treated mice had long-term ovarian tumor control compared to mice whose immune systems could recognize flagellin. Unfortunately, it is still unclear why flagellin disrupts immune therapy, specifically in ovarian cancer. Rutkowski and her team are actively investigating and hoping to develop ways for immune cells to ignore flagellin and enhance immunotherapy.
The discovery of how flagellin inhibits ICI therapy is a major breakthrough in ovarian cancer. It has never been demonstrated that bacterial flagellin influences therapy. This work provides insight into the influence of the microbiome on cancer therapy and has the potential to enhance ovarian cancer treatment in the clinic.
Paper, Cancer Immunology Research, Melanie Rutkowski, University of Virginia