Radiation therapy is a common treatment for cancer patients, but it often falls short of delivering the desired outcomes and can lead to severe side effects. However, new research conducted by the University of Chicago and collaborators suggests that inhibiting a specific protein, YTHDF2 (or Y2), could hold the key to improving the success rate of radiation therapy, both as a standalone treatment and in combination with immunotherapy. This inhibition also has the potential to prevent the progression of metastasis at distant sites.
The study, published on May 25 in Cancer Cell, sheds light on the ability of Y2 to suppress the immune response following radiotherapy. Ralph Weichselbaum, MD, senior author of the study and professor and chair of Radiation and Cellular Oncology at the University of Chicago, stated, "Our results suggest we could diminish immunosuppression, which might make the treatments more effective."
The Challenge of Radiation Therapy and Immunotherapy
One of the primary challenges faced in combining radiation therapy with immunotherapy is the lack of sufficient immune activation or the presence of immunosuppression, or sometimes both. The protein Y2 plays a crucial role in these processes and could serve as a treatment target and biomarker. Patients could be screened after an initial radiation treatment, and if they exhibit high levels of Y2-producing immune cells, a drug could be administered to limit its effects. In fact, the researchers have already developed a candidate drug for this purpose in collaboration with partners in the Department of Chemistry and the Physical Sciences Division at the University of Chicago.
Radiation therapy stimulates positive immune effects, such as increased production of antigen-presenting cells and CD8+ T cells. However, it also has negative effects that dampen the anti-tumor immune response. For instance, myeloid-derived suppressor cells (MDSCs) migrate to the tumor site and block CD8+ T cells, thereby inhibiting the anti-tumor immune response. Additionally, the influx of MDSCs can interfere with immunotherapy.
Understanding Y2's Impact on Immune Response
Through analysis of the results from two clinical cancer trials, researchers observed adverse outcomes when patients' levels of MDSCs increased after radiation therapy. These MDSCs also exhibited an overexpression of Y2 following radiotherapy. Further genetic and epigenetic analysis revealed that the induction of Y2 activated the migratory and immune suppressive functions of MDSCs within the tumor and throughout the body. In several cases, these abundant Y2-expressing cells seemed to facilitate the progression of distant metastasis after local radiation.
Promising Findings in Mouse Models
To validate their findings, the research team utilized mouse models in which the Y2 gene was knocked out in MDSCs. When these mice received radiation therapy for local tumors, the treatment proved to be more effective and prevented the formation of distant tumor metastasis. In these knockout models, the MDSCs were also limited in their ability to migrate into tumors and suppress the immune response.
Collaborating with scientists from the Chinese Academy of Sciences, the team also identified a small molecule called DC-Y13 that effectively blocks Y2, replicating the effects observed with the gene knockouts. When administered to mice, this drug improved responses to both radiotherapy and immune therapy.
The Dual Impact of Radiation Therapy
The results of the study highlighted that radiation therapy had a twofold impact. Firstly, it exhibited improved efficacy in targeting local tumors. Secondly, it seemed to suppress the development of distant metastasis, offering a significant advantage.
In conclusion, the inhibition of the Y2 protein presents an exciting avenue for enhancing the success of radiation therapy, either as a standalone treatment or in combination with immunotherapy.
By suppressing Y2, immunosuppression can be diminished, potentially improving treatment outcomes. The identification of Y2 as both a treatment target and a biomarker allows for personalized treatment approaches based on the patient's Y2 levels. These findings have the potential to revolutionize the field of radiotherapy and significantly impact cancer treatment strategies.