DECEMBER 15, 2023, NEW YORK – Radiation therapy (RT) suppresses a key protein called bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) and activates immune suppressive cells known as myeloid derived suppressor cells (MDSCs) to dampen anti-tumor immune responses and induce resistance to radiotherapy (RT), according to a new study led by Ludwig Chicago’s Liangliang Wang, Hua Laura Liang and Director Ralph Weichselbaum and published in Journal of Clinical Investigation.
MDSCs secrete a variety of immunosuppressors in response to RT, including transforming growth factor-β (TGF-β), which plays a critical role in tumor progression. BAMBI is a mock receptor (or pseudoreceptor) of the TGF-β receptor that is known to suppress TGF-β signaling and is implicated in tumor suppression.
The research team found that relatively high BAMBI expression is associated with prolonged overall survival of patients diagnosed with renal clear cell carcinoma, renal papillary cell carcinoma, pheochromocytoma and paraganglioma, and uterine corpus endometrial carcinoma. In addition, the protein is relatively highly expressed in immune cells like monocytes and macrophages in melanoma and colorectal cancer patients.
The Ludwig Chicago team has previously reported that MDSCs in tumors express high levels of m6A reader protein YTHDF2 following exposure to radiation.
“In the current study, we were able to reproduce these results in another cohort of patient samples. Moreover, we observed a close interaction of YTHDF2 with BAMBI in tumor infiltrating immune cells, indicating YTHDF2 might be playing a critical role in regulating BAMBI’s expression,” said Weichselbaum, who is chair of radiation and cellular oncology at the University of Chicago Medicine.
The team conducted animal studies to test if overexpressing BAMBI in MDSCs could suppress the infiltration of MDSCs into tumors in mice treated with radiotherapy. As expected, viral delivery of BAMBI significantly reduced tumor growth and increased survival in these models. Notably, the researchers report that BAMBI overexpression also improved outcomes of immunotherapy in the irradiated mice.
This summary is derived from a University of Chicago Medicine news release that can be accessed here.