A new study led by researchers at The University of Texas MD Anderson Cancer Centre demonstrated that pre-operative radiation therapy for brain metastases not only targets tumour cells directly but also can activate immune pathways that can make tumours 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 tumour 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 tumour and its microenvironment in order to engage the immune system,” Huse said.

“By enhancing T cell diversity and antigen presentation within tumours, radiation ultimately transforms the immunosuppressed tumour 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 tumours 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 tumour microenvironment is immunologically “cold,” meaning it suppresses immune responses against the tumour.

Additionally, the blood-brain barrier prevents many treatments from even reaching tumours in the brain.

Radiation has emerged as a potential treatment option for brain tumours, 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 characterise the immune microenvironments.

What made radiation therapy effective in the tumour microenvironment?

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

In doing so, radiation therapy increases inflammatory cytokines and upregulates immune checkpoints that make tumours more visible and responsive to immunotherapy.

Additionally, radiation alters blood vessels within tumours 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.

Source: University of Texas M. D. Anderson Cancer Center