Summary: Engineering natural killer (NK) cells to resist immune suppression may enable NK cell–based immunotherapies for glioblastoma by preventing tumor stem cells from blocking NK activity.
Source: M.D. Anderson Cancer Center
Preclinical research from The University of Texas MD Anderson Cancer Center shows that glioblastoma stem cells (GSCs) can be recognized by natural killer (NK) cells but evade destruction by releasing the immune-suppressive protein TGF-β. When researchers deleted the TGF-β receptor TGFBR2 in NK cells, those NK cells became resistant to suppression and regained anti-tumor activity.
Published in the Journal of Clinical Investigation, the study identifies TGF-β signaling as a key mechanism by which GSCs blunt NK cell responses in the brain. The findings point to a potential strategy of combining NK cell therapies with approaches that block TGF-β signaling or genetically engineer NK cells to resist it, with the goal of improving outcomes for patients with glioblastoma.
“There is intense interest in applying immunotherapy to glioblastoma, but success has been limited,” said senior author Katy Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation & Cellular Therapy. “By genetically modifying NK cells to overcome the brain’s immunosuppressive environment, we were able to target and eliminate the tumor-regenerating glioblastoma stem cells. These early results support further development of NK cell approaches in glioblastoma and potentially other solid tumors.”
Glioblastoma is the most common and aggressive primary brain tumor in adults. Existing treatments typically provide only temporary benefit, and relapses are often driven by small, therapy-resistant populations of GSCs. Targeting these stem-like cells is considered essential to achieve durable control of the disease.
Prior studies suggested NK cells could recognize GSCs, but whether NK cells could effectively kill these stem cells in the brain microenvironment was unclear. Rezvani’s team designed experiments to test NK cell activity against patient-derived GSCs and to identify mechanisms of immune evasion within glioblastoma tumors.
Supported by MD Anderson’s Moon Shots Program® and the adoptive cell therapy platform, the research involved collaborations with neurosurgery and neuro-oncology experts. The investigators first confirmed in vitro that donor NK cells kill patient-derived GSCs while sparing normal brain astrocytes, demonstrating target selectivity under controlled conditions.
To determine whether NK cells infiltrate human glioblastoma and remain functional in situ, the team analyzed tumor samples obtained at surgery. Although glioblastoma specimens contained abundant tumor-infiltrating NK (TI-NK) cells, those TI-NK cells isolated from tumors were functionally impaired and failed to kill GSCs in vitro—evidence that the tumor microenvironment suppresses NK cell activity.
Detailed profiling using protein markers and single-cell RNA sequencing revealed that TI-NK cells express signatures of inhibition and immune suppression compared with peripheral blood NK cells from healthy donors. The single-cell data also highlighted activation of the TGF-β signaling pathway in TI-NK cells, pointing to TGF-β as a major suppressive factor within glioblastoma.
Mechanistic studies showed that direct contact between NK cells and GSCs triggers GSCs to produce TGF-β, a response regulated by αν integrin proteins. The TGF-β released by GSCs engages TGFBR2 on NK cells and shuts down their anti-tumor functions. Pharmacologic blockade of TGF-β signaling prevented GSCs from activating this suppressive pathway in NK cells and preserved NK cell activity in vitro.
Using an in vivo model of patient-derived GSCs, the investigators tested therapeutic approaches designed to overcome this suppressive axis. Combining allogeneic (donor) NK cell infusions with inhibitors targeting αν integrins or TGF-β receptors improved tumor control compared with untreated controls. Most notably, adoptive transfer of gene-edited NK cells lacking TGFBR2 produced the strongest anti-tumor effect and significantly extended overall survival compared with unedited NK cells or no treatment.
“Our results support a combined strategy of NK cell–based immunotherapy plus disruption of the TGF-β signaling axis to neutralize glioblastoma stem cell defenses in the brain,” Rezvani said. “These preclinical data provide the rationale for launching a clinical trial to test this experimental approach in patients with glioblastoma.”
Funding: This work was supported by MD Anderson’s Moon Shots Program, the adoptive cell therapy platform, Ann and Clarence Cazalot Jr., the Dr. Marnie Rose Foundation, the Specialized Program of Research Excellence (SPORE) in Brain Cancer (P50CA127001), and grants from the National Institutes of Health (CA016672; CA120813; P30CA16672).
About this glioblastoma brain cancer research news
Source: M.D. Anderson Cancer Center
Contact: Clayton Boldt, Ph.D – M.D. Anderson Cancer Center
Image: The image is in the public domain
Original Research: The study appears in the Journal of Clinical Investigation