MAY 16, 2025, NEW YORK - Researchers led by Ludwig Chicago Co-director Ralph Weichselbaum report in the current issue of Nature that high doses of radiation can fuel the growth of existing metastatic tumors that aren't directly treated with radiation. The study-co-authored by Ludwig Chicago's András Piffkó, Kaiting Yang, Sean Pitroda and Hua Laura Liang, who contributed equally-also describes the mechanisms by which this occurs and preclinically evaluates a strategy by which the effect might be suppressed for the improvement of cancer therapy.
The study began with the analysis of biopsy samples from a clinical trial led by a University of Chicago colleague, Steven Chmura, in which patients with diverse histological types that were treated with high dose focused radiotherapy known as Stereotactic Body Radiotherapy (SBRT) and checkpoint blockade immunotherapy (Pembrolizumab). That trial found that tumors at preexisting metastatic sites increased in size following SBRT, suggesting radiation might promote tumor growth.
Gene expression profiling of trial samples revealed elevated expression of a protein called amphiregulin-which binds and activates the epidermal growth factor receptor (EGFR)- in tumors treated with radiation.
Experiments in animal models of lung and breast cancer, meanwhile, revealed that while radiation reduced the number of new metastases, it increased the growth of tumors at existing metastatic sites and boosted amphiregulin expression in tumor cells and blood. Blocking the protein with antibodies, or deleting its gene in tumor cells, reduced the size of tumors outside the field of radiation.
Examination of blood samples from another clinical trial in which patients received SBRT and immunotherapy showed relatively high levels of amphiregulin in the serum following SBRT-associated with adverse treatment outcomes. Additionally, the researchers found that an increase in immunosuppressive myeloid cells in patients was associated with metastatic progression and death.
Weichselbaum and his colleagues showed that amphiregulin blocks the differentiation of myeloid cells, pushing them into an immunosuppressive state. Amphiregulin and radiation also boosted expression on tumor cells of the CD47 protein, which transmits a "don't eat me" signal that thwarts the ability of macrophages and myeloid cells to engulf tumor cells.
The researchers show that blocking amphiregulin and CD47 in combination with radiotherapy results in highly effective control of metastatic tumors in animal models. The study suggests new strategies for treating cancer patients at various stages of metastatic disease.
"These results open a whole new way of thinking about the systemic effects of radiotherapy," said Weichselbaum, who is also the Daniel K. Ludwig Distinguished Service Professor of Radiation and Cellular Oncology at University of Chicago Medicine. "Based on these findings, we are planning to conduct a clinical trial to further explore and validate the results."
The University of Chicago Medicine press release from which this summary is derived can be found here.
