A groundbreaking study conducted by researchers at the University of Chicago Medicine Comprehensive Cancer Center has discovered a novel therapeutic target that can overcome resistance to radiation therapy in cancer patients. The study, published in the Journal of Clinical Investigation, reveals that radiation therapy suppresses a protein called bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), leading to the activation of immune suppressive cells. These immune suppressive cells, known as myeloid-derived suppressor cells (MDSCs), dampen the function of cancer-fighting immune cells and reduce the effectiveness of radiation therapy, ultimately causing therapy resistance.
Radiation therapy is a commonly used treatment for cancer that kills cancer cells and stimulates immune cells to combat the disease. However, the therapy also recruits MDSCs, which have immunosuppressive properties, thereby limiting the efficacy of radiation therapy. In order to understand the mechanisms underlying MDSC-induced therapy resistance, the research team focused on the role of transforming growth factor-beta (TGF-β), which is secreted by MDSCs in response to radiation therapy and plays a critical role in tumor progression.
Although TGF-β is known to be involved in immune suppression and MDSC migration, directly targeting this protein may lead to undesired side effects due to its widespread expression. Therefore, the researchers decided to investigate factors that regulate TGF-β signaling in MDSCs indirectly. They discovered that BAMBI, a pseudoreceptor that mimics the TGF-β receptor, suppresses TGF-β signaling and is implicated in tumor suppression.
Analyzing transcriptome data from cancer patients, the researchers found that those with higher BAMBI expression had prolonged overall survival in four types of tumors: kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, pheochromocytoma and paraganglioma, and uterine corpus endometrial carcinoma. Additionally, BAMBI was found to be highly expressed in immune cells like monocytes and macrophages compared to other cell populations in melanoma and colorectal cancer patients.
The team observed a significant reduction in BAMBI levels specifically in tumor-infiltrating MDSCs following radiation treatment, which piqued their interest in understanding the underlying mechanism. Previous studies by the team had shown increased levels of a protein called YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2) in MDSCs after radiation. In the current study, they verified these results and discovered a close interaction between YTHDF2 and BAMBI in tumor-infiltrating immune cells, suggesting that YTHDF2 may play a crucial role in regulating BAMBI expression.
To assess the therapeutic potential of BAMBI, the researchers conducted animal studies in which BAMBI was overexpressed in MDSCs. The results were remarkable, as viral delivery of BAMBI significantly suppressed tumor growth and increased survival in mice treated with radiation therapy. Furthermore, BAMBI overexpression also improved the outcomes of immunotherapy in the irradiated mice.
The findings of this study have significant implications for the development of new therapeutic interventions targeting TGF-β. Existing pharmacological interventions have shown toxic and non-specific effects, making novel approaches like BAMBI particularly promising. By indirectly targeting TGF-β and specifically focusing on immune suppressor cells, these therapies have the potential to not only control local tumor growth but also prevent the spread of cancer.
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