Study reveals surprising side effects of high-dose radiation therapy

In a new study published in Nature, researchers at the University of Chicago Medicine Comprehensive Cancer Center explore a surprising phenomenon in which high doses of radiation cause growth in existing metastatic tumors that weren’t directly treated with radiation.

Scientists previously observed that radiation can cause distant tumors to shrink after radiation, known as the “abscopal effect.” The UChicago researchers therefore dubbed the new, opposite response the “badscopal effect,” as a play on words for when unrelated metastatic tumors grow after radiation. 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, termed “oligometastasis.” Scientists believe that radiotherapy activates the immune system, producing regression in tumors at distant sites that are not directly treated with radiation (i.e. 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 progression 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, MD, Chair and Daniel K. Ludwig Distinguished Service Professor of Radiation and Cellular Oncology at UChicago Medicine.

Uncovering the ‘badscopal’ effect

“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.”

To investigate this tumor-to-tumor interaction, the research team analyzed biopsy samples from a clinical trial in which patients with diverse histological types that were treated with high dose focused radiotherapy known as Stereotactic Body Radiotherapy (SBRT) and checkpoint blockade (Pembrolizumab). That clinical trial team, led by Steven Chmura, MD, PhD, Professor of Radiation and Cellular Oncology and 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, MD, 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 a protein called amphiregulin was significantly increased.

Amphiregulin binds to epidermal growth factor receptor (EGFR), a widely expressed transmembrane tyrosine kinase, and activates major intracellular signaling pathways governing cell survival, proliferation, migration and cell death.

The researchers then studied this effect using 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 metastases. Radiotherapy significantly upregulated amphiregulin in tumor cells and blood. Blocking amphiregulin with antibodies or eliminating its gene in the tumor cells using the gene editing technology CRISPR reduced the size of tumors outside of the radiation field.

“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 the mechanism further, the researchers analyzed blood samples from a second clinical trial conducted by Chmura, in which lung cancer patients received SBRT either following or at the same time as immunotherapy. They found that failure to decrease amphiregulin following SBRT in the serum of patients was associated with an adverse outcome. Additionally, they found an increase in myeloid cells with immunosuppressive characteristics was associated with metastasis progression and death.

In a previous study published in Cancer Cell, Weichselbaum and team demonstrated that ablating immunosuppressive myeloid cells reduces both the size and frequency of metastasis in animal models. By contrast, in the current study, they saw an increase in immunosuppressive myeloid cells in animals where amphiregulin was highly expressed in tumors and blood following radiation but not in tumors that did not express amphiregulin. Amphiregulin appeared to block the differentiation of myeloid cells, leading to an immunosuppressive phenotype.

In collaboration with Ronald Rock, PhD, Associate Professor in the Department of Biochemistry at UChicago, the team discovered that amphiregulin and radiation upregulated CD47, a so-called “don’t eat me” signal on tumor cells that blocks the ability of macrophages and myeloid cells to engulf tumor cells.

Blocking amphiregulin and CD47 in combination with radiotherapy resulted in highly effective metastatic control in animal models. The study results indicate a paradigm shift for the use of radiation therapy in patients with locally advanced and metastatic tumors, in which molecules upregulated by radiotherapy could be detected and neutralized. This in turn could lead to a new type of personalized radiotherapy, especially in patients with metastatic disease.

“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.”

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.

Additional authors include András Piffkó from the University of Chicago, USA, and the University Medical Center Hamburg-Eppendorf, Germany; Kaiting Yang from the University of Chicago, the Ludwig Center for Metastasis Research, and South China University of Technology, Guangzhou, P.R. China; Arpit Panda, Janna Heide, Katarzyna Zawieracz, Leonhard Donle, Ernst Lengyel, Ronald Rock, and Everett E. Vokes from the University of Chicago; Krystyna Tesak, Jason Bugno, Chuangyu Wen, Emile Naccasha, Dapeng Chen, Steven Chmura, Sean Pitroda, and Hua Laura Liang from the University of Chicago, and the Ludwig Center for Metastasis Research, Chicago; Chuan He from the Howard Hughes Medical Institute, University of Chicago, Chicago; Liangliang Wang from the University of Chicago, the Ludwig Center for Metastasis Research, Chicago, and Chinese Academy of Sciences, Beijing, P.R. China; Yanbin Fu from the University of Chicago and Weill Cornell Medicine, New York; Douglas Tilley from Temple University, Philadelphia; and Matthias Mack from the University of Regensburg, Regensburg, Germany.