Designed natural killer cells can remove glioblastoma stem cells


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Preclinical research from the MD Anderson Cancer Center at the University of Texas finds that while glioblastoma stem cells (GSCs) may be targeted by natural killer (NK) cells, they are able to evade the attack. immune releasing the TFG-β signaling protein, which blocks NK cellular activity. Suppression of the TFG-β receptor in NK cells, however, made them resistant to this immune suppression and allowed their antitumor activity.

The findings, published today in the Journal of Clinical Research, suggest that NK cell engineering to resist immune suppression may be a feasible path to the use of NK cell-based immunotherapies to treat glioblastoma.

“There is great interest in using immunotherapy to improve treatments for glioblastoma patients, but so far there has been limited success,” said lead author Katy Rezvani, MD, Ph.D., transplant professor of stem cells and cell therapy. “We were able to overcome the immunosuppressive environment of the brain through genetic engineering of NK cells, which were able to eliminate tumor regenerating GSCs. We are encouraged by these early results and look forward to applying similar strategies to explore therapies. with solid tumor type NK cells “.

Glioblastoma is the most common and aggressive form of primary brain tumor in adults. Current treatments are only short-lived, with recurrences driven largely by small therapy-resistant GSC populations. Therefore, it is necessary to develop new treatments that can effectively target GSCs.

Published data suggest that NK cells may be able to target GCS, but it was unclear whether in fact, it would be susceptible to NK cell death, Rezvani explained. Therefore, his team designed the study to evaluate the efficacy of NK cells against GSCs.

Rezvani and his research team have worked to advance NK cells as cancer therapy with support from MD Anderson’s Moon Shots program, a rapidly develop scientific discoveries in significant clinical advances that save patients ’lives. Current work was supported by the adoptive cell therapy platform and the Glioblastoma Moon Shot, in collaboration with Frederick Lang, MD, president of neurosurgery, and Amy Heimberger, MD, now at Northwestern University Feinberg School of Medicine.

The researchers first confirmed that NK cells could target GSC in vitro. Unedited NK cells from healthy donors were able to eliminate GSCs derived from the patient, while normal brain cells, called astrocytes, were not affected.

To explore whether NK cells are able to cross the blood-brain barrier to infiltrate brain tumors, the team examined tumor samples extracted during surgery. Glioblastoma samples contained a large number of NK (TI-NK) cells that infiltrated tumors. However, isolated TI-NK cells were not able to kill GCS in vitro, suggesting that NK cells were suppressed in the brain.

The researchers profiled TI-NK cells to study their level of activity using protein markers and monocellular RNA sequencing. TI-NK cells showed signs of inhibitory responses and immune suppression in relation to NK cells isolated from the blood of healthy donors.

Single-cell analysis also revealed an activation of the TGF-β signaling pathway in TI-NK cells, identifying it as a potential immune suppression mechanism. In fact, blocking TGF-β signaling with various inhibitors prevented GSCs from activating this pathway in NK cells and suppressing NK cell activity.

The study further clarified that GSCs produce TGF-β in response to direct cell-cell contact with NK cells, a process regulated by αν integrin proteins. The TGF-β released by GSCs activates its corresponding receptor on NK cells, TGFBR2, to block its antitumor activity.

Using an in vivo model of patient-derived GSCs, the researchers demonstrated that the combination of donor or allogeneic-derived NK cells with inhibitors targeting αν integrins or TGF-β receptors improved tumor control relative to untreated controls.

More impressive were the results with genetically deleted TGFBR2 allogeneic NK cells. Treatment with these gene-edited NK cells resulted in a significant improvement in overall survival relative to untreated controls or treatment with unedited NK. .

“These findings support a combinatorial approach to NK cell-based immunotherapy along with disruption of the TGF-β signaling axis to overcome GSC immune defenses in the brain,” Rezvani said. “Based on these findings, we are working to launch a clinical trial evaluating this experimental approach as a new treatment for glioblastoma.”

NK cells with bispecific antibody show activity against lymphoma cells

More information:
Hila Shaim et al, Orienting the αv-TGF-β integrin axis improves the natural function of killer cells against glioblastoma stem cells, Journal of Clinical Research(2021). DOI: 10.1172 / JCI142116.

Citation: Designed Natural Killer Cells Can Remove Glioblastoma Stem Cells (2021, June 17) Retrieved June 17, 2021 from cells-glioblastoma-stem.html

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