When glioblastoma is discovered and treated aggressively, it almost always recurs. Without treatment, the median survival with glioblastoma is only a few months, but even with treatment, survival is frequently only around one year. Now, preclinical research from the University of Texas MD Anderson Cancer Center demonstrated that although glioblastoma stem cells (GSCs) can be targeted by natural killer (NK) cells, they are able to evade immune attack by releasing the TFG-β signaling protein, which blocks NK cell activity. Deleting the TFG-β receptor in NK cells, however, rendered them resistant to this immune suppression and enabled their anti-tumor activity.
The findings are published in Journal of Clinical Investigation, in a paper titled, “Targeting the αv integrin-TGF-β axis improves natural killer cell function against glioblastoma stem cells.”
“Glioblastoma, the most aggressive brain cancer, recurs because GSCs are resistant to all standard therapies,” wrote the researchers. “We showed that GSCs, but not normal astrocytes, are sensitive to lysis by healthy allogeneic NK cells in vitro.”
Their findings suggest that engineering NK cells to resist immune suppression may be a feasible path toward using NK cell-based immunotherapies for treating glioblastoma.
“There is tremendous interest in utilizing immunotherapy to improve treatments for patients with glioblastoma, but there has been limited success to date,” explained senior author Katy Rezvani, M.D., Ph.D., professor of stem cell transplantation and cellular therapy. “We were able to overcome the immunosuppressive environment in the brain by genetically engineering NK cells, which were then able to eliminate the tumor-regenerating GSCs. We are encouraged by these early results and hope to apply similar strategies to explore NK cell therapies in additional solid tumor types.”
The researchers have worked to advance NK cells as a cancer therapy with the support of MD Anderson’s Moon Shots Program, a collaborative effort that tackles cancer in three ways: innovation, scale, and collaboration. The current research was supported by the adoptive cell therapy platform and the Glioblastoma Moon Shot, in collaboration with Frederick Lang, M.D., chair of neurosurgery, and Amy Heimberger, M.D., now at Northwestern University Feinberg School of Medicine.
First, the researchers confirmed that NK cells could target GSCs in vitro. They observed that nonedited NK cells from healthy donors were able to eliminate patient-derived GSCs, whereas normal brain cells, called astrocytes, were unaffected.
The researchers examined tumor samples removed during surgery to determine whether NK cells were able to cross the blood-brain barrier. The glioblastoma samples contained high numbers of tumor-infiltrating NK (TI-NK) cells. However, isolated TI-NK cells were unable to kill GCSs in vitro, suggesting that NK cells were suppressed in the brain.
Next, they observed TI-NK cells’ level of activity using protein markers and single-cell RNA sequencing.
“Mass cytometry and single cell RNA sequencing of primary tumor samples revealed that glioblastoma-infiltrating NK cells acquired an altered phenotype associated with impaired lytic function relative to matched peripheral blood NK cells from glioblastoma patients or healthy donors,” wrote the researchers. “We attributed this immune evasion tactic to direct cell-cell contact between GSCs and NK cells via integrin-mediated TGF-β activation.”
The study demonstrates that GSCs produce TGF-β in response to direct cell-cell contact with NK cells. TGF-β released by GSCs activates its corresponding receptor on NK cells, TGFBR2, to block their anti-tumor activity.
The researchers demonstrated that combining donor-derived, or allogeneic, NK cells with inhibitors targeting either αν integrins or TGF-β receptors improved tumor control relative to untreated controls.
“These findings support a combinatorial approach of NK cell-based immunotherapy together with disruption of the TGF-β signaling axis to overcome the immune defenses of GSCs in the brain,” Rezvani said. “Based on these findings, we are working to launch a clinical trial evaluating this experimental approach as a novel treatment for glioblastoma.”
