With GBM, T Cells May Be Stuck in Bone Marrow

Patients with glioblastoma (GBM) often have low levels of T cells circulating in their blood, and a recent study has uncovered a possible explanation (Nat Med 2018;24:1459–68). These “missing” T cells, researchers discovered, are sequestered within the bone marrow in high numbers instead of being properly trafficked to the blood and lymphoid organs, likely because they lack S1P1, a cell-surface receptor. The findings could lead to more-effective treatments for brain cancer.

Peter Fecci, MD, PhD, of Duke University in Durham, NC, the study's senior author, notes that immunotherapy has so far not worked well against primary brain cancers such as GBM, possibly because these tumor types suppress the immune system. “We started to realize over a decade ago that T cells were potentially missing in these folks, and the ones that are there don't work, and you just can't have an effective immunotherapy without T cells,” he says. “My group is focused on trying to understand why that is, with the hope that we can reverse some of those things and take away cancer's ability to sidestep immunity.”

Fecci and his team first confirmed that in patients as well as in mice with GBM, there were significantly fewer circulating CD4+ and CD8+ T cells compared with healthy controls. Conversely, they found that this disappearing act correlated with high T-cell numbers in the bone marrow. Moreover, when the researchers implanted other tumor types—including breast, lung, and melanoma—intracranially into mice, they observed a similar bone marrow accumulation of T cells. This did not happen when the same tumor types were implanted subcutaneously.

“What we think we've discovered is a novel mechanism of ‘immune privilege’—a way that the brain keeps the immune system out,” Fecci says. “These tumors are essentially usurping that mechanism that the brain harbors, and by keeping the immune system away, those tumors are able to thrive.”

Next, the researchers determined that sequestered T cells in patients and mice with GBM lacked S1P1; in fact, high bone marrow T-cell numbers strongly correlated with low S1P1 levels. Focusing on the mouse models, when S1P1 levels were genetically stabilized, the team observed that T-cell sequestration no longer occurred. Treating these mice with a T cell–activating therapy improved survival, and this was further prolonged by adding the PD-1 inhibitor nivolumab (Opdivo; Bristol-Myers Squibb), which had otherwise not been effective as monotherapy.

Michael Lim, MD, director of the Johns Hopkins Brain Tumor Immunotherapy program in Baltimore, MD, who was not involved in the study, considers it a novel and important finding.

“Everyone is so focused on glioblastomas or any brain tumor causing immunosuppression locally, but this paper highlights this paradigm shift in thinking about the entire body being immunosuppressed,” he says. “I think it gives us another strategy in trying to make these tumors responsive to immunotherapy.”

Donald O'Rourke, MD, of the University of Pennsylvania in Philadelphia, who was also not connected to the research, considers it “a great step, because it introduces a new way of thinking, and a new avenue for further research.”

“In the future, if you were able to give a drug under controlled circumstances where you could encourage T-cell egress out of the bone marrow and into the brain, that would be pretty huge,” he says. –Catherine Caruso

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