Improving Immunotherapy for Cancer Patients: Protecting the Brain

Immunotherapies have been a game-changer for cancer treatment, improving life expectancy and survivorship over the past decade, but that doesn’t mean there’s no room for improvement.

“Immune checkpoint inhibitors have transformed cancer treatment by reviving the body’s immune system to better recognize and fight cancer cells,” says Munjal M. Acharya, PhD, an associate professor in the Department of Anatomy & Neurobiology at the UC Irvine School of Medicine. “However, these powerful ICI therapies can sometimes trigger unwanted, often damaging, immune reactions in healthy tissues, including the brain.”

ICI-related unwanted responses in the brain can lead to neurologic events in cancer survivors, such as headaches, seizures, fatigue, encephalitis or Guillain-Barré syndrome.

To better understand how to mitigate potential brain dysfunction following ICI therapies, Acharya and a team of researchers at UC Irvine conducted a study to examine how ICIs affect the hippocampus — a part of the brain central to forming long‑term memories, learning and spatial navigation.

The findings appear in a paper published in Advanced Science, by Devyani Swami, PhD, Suhas Sureshchandra, PhD, Janaki Manoja Vinnakota, PhD, Robert Zeiser, MD, Shivashankar Othy, PhD, and Acharya.

Molecular Underpinnings of ICI-Induced Brain Dysfunction

The study helps define how ICI-associated immune-related adverse events alter the cellular and molecular organization of the brain and disrupt brain function.

“Using high-throughput, spatially resolved molecular assays, we found that ICI distinctly modified the abundance and transcriptional states of neuronal and non-neuronal cells, particularly microglia, astrocytes, oligodendrocytes and T cells in the ICI-treated hippocampal region,” says Swami, a postdoctoral researcher at UC Irvine.

These changes were associated with heightened inflammation and immunological changes. The researchers also observed signs that patients who received ICI therapy had activated microglial cells, the brain’s resident immune cells.

“Using a conditional T cell depletion mouse model that eliminates T cells from the body and brain, we found that T cells are essential for triggering microglial activation following ICI treatment,” says Swami. “Thus, our study provides a detailed map of how brain and immune cells interact during ICI therapy and highlights the essential role of T cells in shaping immune responses within the brain.”

Next Steps

By defining the cellular and molecular landscape of ICI-induced immune-related adverse events in the brain, these findings may help identify the cell populations and cell-specific genes most vulnerable to treatment.

“This could support the development of more targeted strategies to reduce microglial activation and neuroinflammation while preserving the anti-tumor benefits of ICI therapy,” says Othy, an assistant professor in the Department of Physiology & Biophysics. The team is already working toward this goal.

“Future studies investigating interactions between non-neuronal cells and inflammatory immune cells in other brain regions, particularly the prefrontal cortex, choroid plexus and meninges, are underway,” says Othy. “We want to better understand how these cellular crosstalk networks contribute to neuroinflammation and cognitive dysfunction following ICI treatment.”

This work was supported by funding from the National Institutes of Health (NIH) and the UC Irvine Chao Family Comprehensive Cancer Center.

— Shani Murray