Researchers have provided novel insights into the effects of radiation on the immune cells surrounding breast cancer tumors, according to a recent study published by Yoneyama et al in the International Journal of Radiation Oncology • Biology • Physics. The findings revealed that the relationship between the tumor-immune microenvironment and radiation may be more complex than previously understood.
Background
There is increasing interest in the potential of radiotherapy to prime a patient’s body for treatment by making their cancer more receptive to immunotherapy. Other research has suggested that radiotherapy may be capable of switching ‘cold’ tumors—which are resistant to immunotherapy and must be treated with traditional therapies such as chemotherapy—to ‘hot’ tumors.
The two types of tumors can be differentiated by identifying lymphocytes known as T cells. ‘Hot’ tumors exhibit tumor-infiltrating lymphocytes, demonstrating that the immune system has recognized the cancerous cells and is working to destroy them. Researchers often use tumor-infiltrating lymphocytes as a marker of survival in several types of cancers.
Prior research has suggested that radiotherapy can enhance the number of tumor-infiltrating lymphocytes in tumors. Although it is widely believed that neoadjuvant radiotherapy may increase the likelihood of a positive outcome following immunotherapy, some preclinical studies have found that radiotherapy may suppress the body’s immune response, thereby reducing the efficacy of immunotherapy.
Previous research has been limited by the current standard of care in breast cancer in which radiotherapy is routinely delivered to a patient following surgical resection of the tumor. This approach has only allowed researchers to evaluate the effects of irradiating the cancerous cells in a laboratory setting, where the tumor-immune microenvironment can’t be considered.
Study Methods and Results
Researchers assessed the relationship between the tumor–immune microenvironment and radiation in the preoperative setting with doses that are routinely used in the postoperative setting. Because the tumors were still in vivo, the effects of radiotherapy on the tumor-immune microenvironment could be determined more clearly.
The team used blood and tumor samples from two United Kingdom–based clinical studies—the PRADA and Neo-RT trials—investigating neoadjuvant radiotherapy in 43 patients with nonmetastatic breast cancer of various subtypes. The samples were taken at multiple timepoints throughout the trials, providing an opportunity to detect any differences between the pre-, during, and postradiotherapy samples.
The researchers then allocated scores to the patient samples based on the number of tumor-infiltrating lymphocytes located in certain regions of the tissue. They noted that higher scores correlated with specific breast cancer subtypes, with patients who had HER2-positive or triple-negative breast cancer more likely to have increased lymphocyte infiltration. Additionally, higher scores were identified in patients with higher grades of breast cancer.
After assessing changes to these scores over time, neoadjuvant radiotherapy appeared to contribute to the sustained loss of tumor-infiltrating lymphocytes from the tumor-immune microenvironment in both the breast and the peripheral bloodstream. Notably, the levels of these cells did not recover by the time of surgery.
The researchers drew particular attention to the routine delivery of radiotherapy to the regional lymph nodes in patients with breast cancer. They noted that this strategy may be impairing immune activity, and suggested that preserving the lymph nodes could be critical to the effective combination and sequencing of radiotherapy with immune checkpoint blockade prior to surgery.
Conclusions
“Our study represents a major advance in our understanding of the dynamics of [tumor-infiltrating lymphocytes] in response to radiotherapy in breast cancer. Despite the explosion of interest in the immunogenic potential of radiotherapy, a huge gap has persisted in our knowledge about the effect of radiation alone on the breast [tumor-immune microenvironment],” detailed senior study author Navita Somaiah, DPhil, Group Leader of the Translational Breast Radiobiology Group at the Institute of Cancer Research and an honorary consultant clinical oncologist in the Breast Unit at The Royal Marsden National Health Service Foundation Trust. “This work has started to close that gap, but it also highlights the need for deeper interrogation of factors such as dose fractionation, the timing of radiotherapy, and volumes irradiated, so that we can optimize radiation-induced immunogenic cell death,” she highlighted.
The findings may have clinical implications, particularly in relation to the design of future radiotherapy clinical trials. In the longer term, the researchers indicated that the results of their study could lead to the development of more effective combination therapies involving radiotherapy and immunotherapy, which could improve outcomes in patients with high-risk breast cancer.
The researchers emphasized that further studies are needed to determine how to use radiotherapy to maximize the benefits of other treatments such as immunotherapy.
“The recent trials testing the safety of [neoadjuvant radiotherapy] in breast cancer gave us a unique opportunity to test the effects of radiotherapy in vivo. Our data set represents a unique insight into the relationship between radiation and [the tumor-immune microenvironment], and it brings into question the widely held belief that radiotherapy converts immunologically ‘cold’ tumors into ‘hot’ tumors,” said co–lead study author Miki Yoneyama, BSc, a PhD student in the Translational Breast Radiobiology Group at the Institute of Cancer Research. “Our findings will likely contribute to the ongoing debate about the merits of lymph node irradiation for patients receiving immunotherapies. We hope that further exploration of this complex area of radiobiology will ultimately lead to improved outcomes for everyone living with breast cancer.”
Disclosure: The research in this study was funded by the Institute of Cancer Research. For full disclosures of the study authors, visit redjournal.org.
