A newly defined parameter may help explain why certain immunotherapies for brain tumors fail and therefore offer new opportunities to curb tumor progression, according to research led by Peter Fecci, MD, PhD, director of the Duke Center for Brain and Spine Metastasis.

In an article published in Immunity, Fecci and his team provide new insight into the mechanisms underlying a key reason that immunotherapies fail in brain tumors and other cancers: T-cell exhaustion. They show that what causes this exhaustion is not the tumor itself, but instead the infiltrating macrophages.

“For years, many have presumed that suboptimal interactions between T cells and tumor cells are the direct cause of T-cell exhaustion within the tumor microenvironment,” said Fecci. “It’s really tumor-infiltrating macrophages that do the dirty work here. We specifically highlight the role that macrophage antigen presentation to T cells appears to play.”

Additionally, the Fecci Lab has defined a new T-cell exhaustion parameter that appears to reflect how likely it is for an immunotherapy to work in a given tumor. That metric, the intratumoral progenitor exhaustion-to-terminal exhaustion ratio (PETER), can decrease with tumor progression in solid cancer, based on the lab’s findings. Likewise, increasing the PETER in a tumor appears to make it more susceptible to immunotherapy.

By finding a way to remove or target macrophages and increase the PETER in patients with brain tumors, providers can seemingly license immunotherapies to become more effective, Fecci explained.

“The implication here is that we may have a new road map for how to counter T-cell exhaustion and remove some of the barriers to immunotherapeutic success,” Fecci said. “This would be especially powerful in the case of many brain tumors, where immunotherapy hasn’t been particularly successful to date. We’re excited to get to work and see what impact we can have here.”