Up to 60 percent of cancer patients receive radiation therapy, but it’s not always effective. These treatments fail because the tumor grows back at the site of the original tumor, or the tumor metastasizes to another part of the body. A new study from University of Chicago hopes to overcome resistance to radiation therapy by inhibiting a key protein, bringing the immune system into the fight.
The study, published in the May 25 issue of Cancer Cell, shows how drug therapy that inhibits YTHDF2 (or Y2) improves outcomes with radiation therapy alone or in combination with immunotherapy. YTHDF2 is a protein that suppresses the immune response after radiation therapy. This treatment also prevented the progression of distant metastases after local radiotherapy, making Y2 a promising target for future combination therapy programs.
Professor Ralph Weichselbaum of the University of Chicago said, “These findings have potential clinical implications because not only can we enhance the local effects of radiation, but we can also eliminate these adverse long-range effects of radiation, and I think these findings may change the practice of radiation therapy.”
Radiation therapy sometimes produces what is known as an abscopal effect, in which radiation to one part of the tumor also causes the tumor in another part of the body to shrink. This phenomenon is rare, but it is thought to be related to the activation of the immune system. Radiation stimulates positive immune effects, such as the generation of more antigen-presenting cells and CD8+ T cells, as well as the negative effects of suppressing antitumor immune responses. A type of blood cell called myeloid-derived suppressor cells (MDSCs) migrates to the tumor site and dampens the antitumor immune response by blocking the antitumor effects of CD8+ T cells. The influx of MDSCs can also interfere with immunotherapy, which aims to unleash the immune system to fight tumors.
Chuan He, PhD, et al. analyzed the results of two clinical trials of cancer patients conducted by Steven Chmura, MD, professor of radiation and cellular oncology, and colleagues. The researchers observed that after radiation therapy, when patients’ levels of MDSCs rose, they experienced adverse outcomes. After radiotherapy, MDSCs also overexpressed Y2. Genetic and epigenetic analyzes revealed that Y2 induction activated the migration and immunosuppressive functions of MDSCs in tumors and throughout the body. Amazingly, this topical treatment has effects all over the body.
In many cases, these abundant, Y2-expressing cells also appeared to develop distant metastases after focal radiation, an effect Weichselbaum termed a “bad-scopal” effect. “This effect has been underestimated, but it appears to be more common than the abscopal effect.”
He is a renowned biochemist who studies how chemical modifications of DNA and RNA dynamically alter their expression. In a 2019 study with Weichselbaum, their team showed that a related protein called YTHDF1 (Y1) also interferes with immunotherapy, and that when it is blocked, the immune system is better able to fight tumors. Y1 and Y2 are used to identify RNA modifications and regulate biological processes. Y1 promotes the translation of mRNA into protein; Y2 degrades mRNA, but its role in immune cells related to radiotherapy and immunotherapy has not been explored in depth.
In the new study, the team, led by Liangliang Wang, Ph.D., a researcher in Weikselbaum’s lab, used a mouse model in which the gene that produces Y2 was knocked out in MDSCs. When these mice received radiation therapy to local tumors, the treatment was more effective and prevented the “bad-scopal” effect that allows distant tumors to metastasize. In these Y2-inhibited models, the ability of MDSCs to migrate to tumors and suppress immune responses was also limited.
Working with colleagues from the Chinese Academy of Sciences, the team also discovered a small molecule called DC-Y13, which blocks Y2 and replicates the effect of the gene knockout. When given to mice, the drug improved responses to radiation therapy and immunotherapy, similar to the Y2 gene deletion.
“What you saw was that radiation worked better for local tumors, and it also seemed to suppress the development of distant metastases,” Weichselbaum said. “So, arguably, it’s a double play for us.”
Weichselbaum believes that Y2 can play an important role as a therapeutic target and biomarker. For example, patients could be screened after initial radiation therapy, and if they have high levels of Y2-producing MDSCs, they could be given drugs to limit their effects. This strategy could be combined with other treatments, such as immunotherapy, or using nanoparticles to deliver drug compounds directly to tumors.
