Researchers at The University of Texas MD Anderson Cancer Center announced on June 17 that pre-operative radiation therapy for brain metastases can both target tumor cells directly and activate immune pathways, potentially making tumors more receptive to immunotherapy. The study, published in Clinical Cancer Research, indicated that radiation therapy eliminates tumor cells and reshapes the surrounding immune landscape by recruiting and activating T cells. This suggests that combining radiation with immunotherapy could improve patient outcomes. The results also identified T cell receptor diversity in the tumor microenvironment as a possible prognostic biomarker for predicting treatment response.
The research was co-led by Jason Huse, M.D., Ph.D., professor of Anatomic Pathology; Nuhad Ibrahim, M.D., professor of Breast Medical Oncology; and Alexandre Reuben, Ph.D., assistant professor of Thoracic/Head & Neck Medical Oncology. Huse said, "Brain metastases are highly complex, and effective treatment requires addressing both the tumor and its microenvironment in order to engage the immune system. By enhancing T cell diversity and antigen presentation within tumors, radiation ultimately transforms the immunosuppressed tumor microenvironment into a more responsive one, providing a strong biological rationale for radiation-immunotherapy combination strategies to improve patient outcomes."
Brain metastases remain a significant clinical challenge due to limited treatment options and poor survival rates. Many cancers respond to immunotherapy; however, the brain tumor microenvironment often suppresses immune responses against tumors. Additionally, the blood-brain barrier restricts many treatments from reaching brain tumors.
To investigate how radiation affects these challenges, researchers conducted an integrated profiling analysis using RNA and T cell receptor sequencing on tissue samples from 306 patients with brain metastases originating from breast or lung cancer. Patient samples from an ongoing clinical trial led by Debra Nana Yeboa, M.D., were also studied to compare pre- and postoperative radiation therapy effects on immune microenvironments.
The study found that radiation damages tumor DNA directly but also causes release of antigens that enhance recruitment and activation of cytotoxic T cells into tumors. Radiation increases inflammatory cytokines and upregulates immune checkpoints while altering blood vessels within tumors to facilitate immune cell entry.
Ibrahim said, "Rather than the traditional approach focused on overcoming the blood-brain barrier for systemic therapy, these results show that it may be more beneficial to shift the focus to the microenvironment of the metastatic brain lesion. Not only does it improve the outcomes of immunotherapy, but it potentially extends those benefits to other areas that are not directly involved in radiation, which is a step in the right direction," the research team plans further validation through larger prospective clinical trials.
