UT MD Anderson at ASTRO

• Brain metastases are difficult to treat, in part due to the immunosuppressive tumor microenvironment and blood brain barrier, making immunotherapy ineffective
• Radiation therapy is used to treat brain tumors, but little is known about how it affects the immune microenvironment
• Radiation acts as an immunomodulator, enhancing T cell receptor diversity and activating immune signatures that are normally suppressed
• Researchers suggest focusing on the brain metastases tumor microenvironment and using radiation in combination with immunotherapy could potentially improve outcomes

A new study led by researchers at The University of Texas MD Anderson Cancer Center demonstrated that pre-operative radiation therapy for brain metastases not only targets tumor cells directly but also can activate immune pathways that can make tumors more receptive to immunotherapy.

The study, published in Clinical Cancer Research, showed that radiation therapy is effective in both eliminating cells directly and also acting to reshape the surrounding immune landscape by recruiting and activating T cells, suggesting that radiation-immunotherapy combination strategies could potentially improve patient outcomes. The results also highlighted T cell receptor diversity in the tumor microenvironment as a potential 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.

“Brain metastases are highly complex, and effective treatment requires addressing both the tumor and its microenvironment in order to engage the immune system,” Huse said. “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.”

Why are brain metastases so hard to treat?

Brain metastases, which are tumors that spread to the brain from cancers elsewhere in the body, remain a major clinical challenge, with limited treatment options and poor survival outcomes. While many cancers respond to immunotherapy, the brain tumor microenvironment is immunologically “cold,” meaning it suppresses immune responses against the tumor. Additionally, the blood-brain barrier prevents many treatments from even reaching tumors in the brain.

Radiation has emerged as a potential treatment option for brain tumors, including brain metastases, showing that it is associated with antitumor immune responses. However, it is not yet clear what specific immune pathways and components are activated by this approach.

To investigate, the researchers conducted an integrated profiling analysis using RNA and T cell receptor sequencing in tissue samples from 306 patients with brain metastases that arose from either breast or lung cancer. Additionally, the researchers studied patient samples from an ongoing clinical trial led by Debra Nana Yeboa, M.D., associate professor of Central Nervous System Radiation Oncology, which compared pre- and postoperative radiation therapy, to further characterize the immune microenvironments.

What made radiation therapy effective in the tumor microenvironment?

Radiation therapy is effective because it not only directly damages tumor DNA, but it also causes tumor cells to react in a way that releases antigens, or “danger signals.” These signals enhance the recruitment and activation of cytotoxic T cells into tumors, resulting in a stronger, targeted response.

In doing so, radiation therapy increases inflammatory cytokines and upregulates immune checkpoints that make tumors more visible and responsive to immunotherapy. Additionally, radiation alters blood vessels within tumors to facilitate immune cell entry and reduces or reprograms suppressive myeloid cells.    

“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,” Ibrahim said. “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.”  

What do these results mean for patients?

While these results are retrospective and observational, the research team currently is looking at validating these findings in larger, prospective clinical trials to explore the potential of combining radiation and immunotherapy as therapeutic strategies in patients with brain metastases. Overall, these results suggest that T cell diversity could be a good way to determine which patients are more likely to respond to the combination of radiation and immunotherapy.

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This work was supported by the Richard Spencer Lewis Memorial Foundation, the Sheila & Merrill Wynne Breast Cancer Research Fund, the Brockman Foundation, the Robert Wood Johnson Foundation, and the UT MD Anderson Brain Cancer Specialized Program of Research Excellence. A full list of collaborating authors and their disclosures can be found with the full paper in Clinical Cancer Research.