Bibliographic Details
| Title: |
Temozolomide and the PARP Inhibitor Niraparib Enhance Expression of Natural Killer Group 2D Ligand ULBP1 and Gamma-Delta T Cell Cytotoxicity in Glioblastoma. |
| Authors: |
Jones, Amber B., Tuy, Kaysaw, Hawkins, Cyntanna C., Quinn, Colin H., Saad, Joelle, Gary, Sam E., Beierle, Elizabeth A., Ding, Lei, Rochlin, Kate M., Lamb, Lawrence S., Hjelmeland, Anita B. |
| Source: |
Cancers; Aug2024, Vol. 16 Issue 16, p2852, 13p |
| Subject Terms: |
COMBINATION drug therapy, GLIOMAS, KILLER cells, T cells, IMMUNOSUPPRESSIVE agents, RESEARCH funding, TEMOZOLOMIDE, ENZYME inhibitors, ANTINEOPLASTIC agents, BLOOD-brain barrier, IMMUNOTHERAPY, IMMUNODIAGNOSIS, CANCER patients, TREATMENT effectiveness, CELLULAR therapy, GENE expression, CELL survival, CELL surface antigens, CELL receptors, IMMUNITY, IMMUNOSUPPRESSION, PHARMACODYNAMICS |
| Abstract: |
Simple Summary: The urgent need for novel therapies for glioblastoma (GBM) treatment may be met through an increased understanding of immune escape and improved immunotherapies. Immune escape can be caused by reduced expression of NKG2D ligands (NKG2DL) on tumor cells that are recognized by natural killer or cytotoxic T cells. While DNA damage from therapeutics can increase NKG2DL ligands to enable immune cell recognition, the immunosuppressive side effects of chemotherapies may limit this potential benefit, especially in the absence of immunotherapy interventions such as gamma delta T cells. PARP inhibitors sensitize cancer cells to temozolomide-induced cell death, and the combination is in clinical trials for GBM. We find that temozolomide and the PARP inhibitor, niraparib, can increase NKG2DL in GBM cells derived from multiple PDXs and increase GBM cell killing by gamma delta T cells in cells derived from a GBM PDX. We suggest capitalizing on transient chemotherapy-induced upregulation of NKG2DL by the combination of temozolomide and PARP inhibition in the appropriate immunotherapy setting for GBM treatment. Glioblastoma (GBM) is an immunologically cold tumor, but several immunotherapy-based strategies show promise, including the administration of ex vivo expanded and activated cytotoxic gamma delta T cells. Cytotoxicity is partially mediated through interactions with natural killer group 2D ligands (NKG2DL) on tumor cells. We sought to determine whether the addition of the blood–brain barrier penetrant PARP inhibitor niraparib to the standard of care DNA alkylator temozolomide (TMZ) could upregulate NKG2DL, thereby improving immune cell recognition. Changes in viability were consistent with prior publications as there was a growth inhibitory effect of the combination of TMZ and niraparib. However, decreases in viability did not always correlate with changes in NKG2DL mRNA. ULBP1/Mult-1 mRNA was increased with the combination therapy in comparison to either drug alone in two of the three cell types tested, even though viability was consistently decreased. mRNA expression correlated with protein levels and ULBP1/MULT-1 cell surface protein was significantly increased with TMZ and niraparib treatment in four of the five cell types tested. Gamma delta T cell-mediated cytotoxicity at a 10:1 effector-to-target ratio was significantly increased upon pretreatment of cells derived from a GBM PDX with TMZ and niraparib in comparison to the control or either drug alone. Together, these data demonstrate that the combination of PARP inhibition, DNA alkylation, and gamma delta T cell therapy has the potential for the treatment of GBM. [ABSTRACT FROM AUTHOR] |
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