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Non-Canonical NF-kB Pathway Improves Radiotherapy Results

Credit: Rhoda Baer (courtesy of NCI)

A new study published in Immunity demonstrates that radiation therapy interacts with a patient's innate and adaptive immune responses to improve cancer treatment differently than previously thought.

In recent years, researchers have discovered that radiotherapy does more than simply attack tumor cells; it also causes secondary immune responses that can greatly enhance anti-tumor immunity. A focus of investigation in these secondary immune responses has been the nuclear factor-kB (NF-kB) signaling pathway, which plays an important role in regulating innate and adaptive immune responses.

NF-kB1, the version of the NF-kB pathway known as the canonical pathway, has been considered a significant regulator of the immune system's B cells. For this reason, a good deal of pharmaceutical research has focused on inhibiting NF-kB1. However, this strategy does not necessarily lead to effective treatment. "Despite extensive investigation, earlier results from these studies failed to improve the response to radiotherapy in animals or humans," explained senior study author Ralph Weichselbaum, MD, professor and chairman of radiation oncology at the University of Chicago.

The research teams, led by Dr. Weichselbaum and by Yang Xin Fu, MD, PhD, professor of pathology at the University of Texas Southwestern Medical Center, discovered the explanation for these prior studies' poor results: disrupting the canonical pathway inhibits the immune system instead of strengthening it, thereby reducing rather than enhancing the effectiveness of radiotherapy. In contrast, inhibiting the other version of the NF-kB pathway, the "non-canonical" pathway, augments the immune system's ability to interact with radiation, improving radiotherapy's efficacy. The researchers reached this conclusion through biochemical studies and genetic models in mice. Blocking the canonical NF-kB pathway caused tumors in mice to worsen, whereas blocking the non-canonical pathway enabled radiotherapy to destroy the tumors more effectively.

"The host immune system seems to have a lot to do with whether or not radiation works," remarked Dr. Fu. "So by blocking that alternative pathway, rather than the pathway everyone's been focusing on, we think we can get better radio-sensitizing agents and better results."

According to Dr. Fu, the study results demonstrate that radiation therapy relies on a process of DNA damage and repair. Dr. Weichselbaum further explained this phenomenon: "When we irradiate tumor cells, the immune system essentially gobbles up the DNA they release." He commented that the tumor's damaged DNA "is seen by the immune system as almost like a virus. The immune system responds as if it were a viral infection, which boosts the overall response. We think this could lead to a whole new therapeutic strategy. Our mice are often cured."

The researchers now seek ways to replicate this strategy in human patients. Stating that adding checkpoint inhibitors improves treatment results even more, Dr. Weichselbaum remarked, "This could become a novel combination approach to improving cancer treatment."

For More Information

Hou Y, Liang H, Rao E, et al (2018). Non-canonical NF-κB antagonizes STING sensor-mediated DNA sensing in radiotherapy. Immunity. [Epub ahead of print] DOI:10.1016/j.immuni.2018.07.008

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