Researchers from the University of Chicago Medicine Comprehensive Cancer Center recently published a study in Cancer Clinical Research describing how radiation can suppress cancer-killing immune responses and how immunotherapies can overcome this suppression.
Radiotherapy is a common cancer treatment that uses electromagnetic radiation to kill tumor cells. According to the American Cancer Society, over 50% of cancer patients will receive some form of radiation therapy during their treatment. Radiation can be given alone or in combination with surgery, chemotherapy, or immunotherapy treatments. In addition to killing tumor cells, radiotherapy can directly affect healthy cells, including cells of the immune system.
The light and dark sides of radiation in immune responses
Ralph Weischelbaum, MD, the Daniel K. Ludwig Distinguished Service Professor and Chair of Radiation and Cellular Oncology, studies the effects of radiotherapy on the immune system. Activating the immune system is an effective way of treating cancer. Radiotherapy can have both immune-activating and immune-suppressing effects, but it is difficult to study these effects independently. Moreover, understanding and controlling the immune-suppressive effects of radiotherapy would be beneficial for cancer patients.
Ralph R. Weichselbaum, MD
Chair of Radiation and Cellular Oncology
Daniel K. Ludwig Distinguished Service Professor of Radiation and Cellular Oncology
of Committee on Cancer Biology
of Committee on Clinical Pharmacology and Pharmacogenomics
Hua Laura Liang, PhD, a Research Associate Professor in the Weischelbaum lab, focuses on the immune-suppressing effects of radiation. She found a clever way to study the “dark side” of radiotherapy that suppresses the immune system using a “two-tumor model.” In this system, one mouse has two tumors from completely different sources: one on their left side and one on their right side. Because the tumors are from different sources, a specific immune response to one tumor will not affect the tumor on the opposite side. This allows researchers to investigate effects on the tumor that are only related to the effects of radiation, not the effects of antigen-specific immune responses.
The abscopal effect and the “bad-scopal” effect
A rare phenomenon observed in radiotherapy treatment is called the abscopal effect. The abscopal effect, when radiating a single tumor can lead to immune responses to distant, non-irradiated tumors, can occur because of the positive effects of radiation on cancer-killing cells called T cells. The two-tumor model allows Liang to ask specific questions about the abscopal effect.
“If you irradiate one site, you can get a systemic effect,” Weischelbaum explains, but these effects of radiation are not all positive. “If there is an abscopal effect, there must be a bad-scopal effect.”
Cancers frequently use many different strategies to hide from the immune system. These methods include recruiting suppressive immune cells like myeloid derived suppressor cells (MDSCs) and increasing expression of the protein PD-L1 on the surface of cells. Cancer immunotherapies, such as immune checkpoint blockade (ICB), curb the PD-L1 protein so that tumor cells can not use it to hide from the immune system. Because PD-L1 is so commonly used by tumors to evade immune cell killing, Liang looked for PD-L1 expression in the mouse after local radiation of only one of the two tumors.
Countering the bad effects of radiation
“PD-L1 was induced by radiation in all the sites that we checked,” Liang said, even if the tissues were not exposed directly to radiation.
This included the lungs, which also showed signs of tumor metastasis from the tumor that did not receive radiation. This could be blocked with ICB, but Liang also wanted to know what was causing the increase of PD-L1 in the lung. “We saw CXCL10 concentration increased in the serum, so we tried to block it,” said Liang. CXCL10 is a protein that attracts certain types of immune cells, including tumor-promoting MDSCs. Liang saw that blocking CXCL10 not only prevented PD-L1 expression in the lung, but it also prevented metastasis from forming.
“MDSCs are bringing PD-L1 into the lung,” Liang said, “but when we block these two factors (PD-L1 and MDSCs), we see that tumor growth is really inhibited, and the lung metastases are decreased.”
This finding might begin to answer the question of why the abscopal effect is so rarely seen. “PD-L1 positive MDSCs enhancing colonization of lung metastasis starts to paint a picture of the negative effects of local radiation,” Weischelbaum explains. However, there are effective strategies to counter the “bad-scopal” effect, including immunotherapies like anti-PD-L1. Weischelbaum suggests that checking patients for increased PD-L1 after radiotherapy is a good first step. “If PD-L1 goes up,” he says, “you want to block it.”
Liang is interested in seeing how these findings might be applied to other cancer treatments. She said, “We wonder what other treatments, like chemotherapy, might affect the expression or induction of PD-L1.”
The study “Radiotherapy Enhances Metastasis Through Immune Suppression by inducing PD-L1 and MDSC in distal sites” was published in Clinical Cancer Research on March 1, 2024, and supported by the National Institutes of Health, The Ludwig Cancer Research Foundation, and the University of Chicago Medicine Comprehensive Cancer Center.
Additional study authors include Yuzhu Hou, Kaiting Yang, Liangliang Wang, Jiaai Wang, Xiaona Huang, Andras Piffko, Sean Z. Luo, Xinshuang Yu, Enyu Rao, Carlos Martinez, Jason Bugno, Everett E. Vokes, Sean P. Pitroda, and Steven J. Chmura from the University of Chicago, and Matthias Mack from University Hospital Regensburg in Germany.
