A new study from the University of Chicago Medicine Comprehensive Cancer Center reveals that radiation therapy can spur growth in untreated metastatic tumors—even if they’re distant from the site being treated.
Scientists have long observed the “abscopal effect,” in which radiation to one tumor causes other, untreated tumors to shrink. But the UChicago team saw the opposite, with untreated metastatic tumors growing with high dose radiation. In a play on words, they dubbed this response the “badscopal effect.”
They believe this unexpected response happens because high dose radiation increases the production of a protein called amphiregulin by tumor cells that are directly treated with radiation. High amounts of amphiregulin weaken the immune system’s ability to fight cancer and make cancer cells better at protecting themselves.
The findings point to promising new therapeutic strategies that could lead to more effective treatments for metastatic cancer.
Radiotherapy: A double-edged sword?
Radiotherapy is often used alone or in combination with surgery and chemotherapy to control localized tumors. More recently, radiotherapy has been used to treat cancers that have limited spread, a condition known as oligometastasis.
Scientists believe radiotherapy activates the immune system, producing regression in tumors at distant sites that are not directly treated with radiation, as in the abscopal effect. However, many patients who receive radiation for oligometastasis or as part of an immunotherapy regimen fail to respond to treatment because of the growth of distant metastasis.
“Our lab postulated that high doses of radiation might actually promote tumor growth at unirradiated sites under certain conditions, potentially accounting for some of these failures,” said senior author Ralph Weichselbaum, chair and Daniel K. Ludwig Distinguished Service Professor of Radiation and Cellular Oncology at UChicago Medicine.
“Studies from the 1940s suggested radiation might cause tumor spread, but that never made sense to me because radiation is a highly effective anti-cancer agent within the tumor bed,” Weichselbaum said. “However, the communication between the irradiated site and distant metastatic sites is fascinating.”
Uncovering the ‘badscopal’ effect
To investigate this tumor-to-tumor interaction, the research team analyzed biopsy samples from a clinical trial in which patients with different types of cancer treated with high dose focused radiotherapy known as Stereotactic Body Radiotherapy (SBRT) and checkpoint blockade.
That clinical trial team, led by Prof. Steven Chmura, the director of Clinical and Translational Research for Radiation Oncology at UChicago, found that tumors at preexisting metastatic sites increased in size following SBRT, suggesting radiation might promote tumor growth.
To understand how radiation at the primary site affects distant tumors, researchers led by András Piffkó, a post-doctoral fellow in the Weichselbaum lab, conducted gene expression profiling of patient tumors before and after radiation treatment. They discovered that in tumors that had been treated with radiation, the gene encoding for amphiregulin was significantly increased.
Amphiregulin in turn binds to EGFR, a receptor protein on tumor cell membranes, and turns on major intracellular signaling pathways governing cell survival, proliferation, migration and cell death.
The researchers studied this effect in animal models of lung and breast cancer. They found that while radiation reduced the number of new metastatic sites, it increased the growth of existing ones.
Radiotherapy significantly increased amphiregulin in both tumor cells and blood. But when researchers blocked amphiregulin with antibodies—or deleted its gene in tumor cells using CRISPR technology—tumors outside the radiation field shrank.
“Interestingly, the combination of radiation and amphiregulin blockade decreased both tumor size and the number of metastatic sites,” Weichselbaum said.
The role of immune suppression
To explore this further, the researchers analyzed blood samples from a second clinical trial conducted by Chmura in which lung cancer patients received SBRT either after or at the same time as immunotherapy.
They found that failure to decrease amphiregulin following SBRT was associated with worse outcomes. They also found an increase in certain immune cells that suppress the body’s defenses was linked to cancer spread and death.
In a previous study published in Cancer Cell, Weichselbaum and his team showed that removing some of these suppressive immune cells reduces both the size and number of metastases. In the new study, they saw more of these suppressive cells in animals with high levels of amphiregulin in their tumors and blood after radiation—but not in those without it.
The findings suggest that amphiregulin may disrupt how immune cells develop, steering them toward an immunosuppressive form that allows tumors to grow.
Working with UChicago biochemistry Assoc. Prof. Ronald Rock, the team discovered that amphiregulin and radiation increased a protein called CD47, a so-called “don’t eat me” signal that helps tumor cells evade immune cells such as macrophages and other myeloid cells.
Blocking both amphiregulin and CD47 along with radiotherapy led to strong control of metastatic tumors in animal models. The findings suggest a new approach to radiation therapy—one in which molecules triggered by radiation are identified and targeted, potentially paving the way for more personalized therapies for patients with metastatic cancers.
“These results open a whole new way of thinking about the systemic effects of radiotherapy,” Weichselbaum said. “Based on these findings, we are planning to conduct a clinical trial to further explore and validate the results.”
Story originally published here with UChicago Medicine.
The study, “Radiation-induced amphiregulin drives tumor metastasis,” was supported by the National Cancer Institute, Ludwig Foundation, the Chicago Tumor Institute, generous gifts from Mr. and Mrs. Vincent Foglia and the Foglia Foundation, Mr. and Mrs. David Kozin and Mr. and Mrs. James Weichselbaum.