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Isolation and Flow Cytometric Analysis of Glioma-infiltrating Peripheral Blood Mononuclear Cells
Published on: November 28, 2015
Inhibition of protein phosphatase-2A with LB-100 enhances antitumor immunity against glioblastoma
Dominic Maggio1, Winson S Ho2,3, Rebecca Breese1
1Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA.
Purpose:
Glioblastoma (GBM) carries a dismal prognosis despite standard multimodal treatment with surgery, chemotherapy and radiation. Immune checkpoint inhibitors, such as PD1 blockade, for treatment of GBM failed to show clinical benefit. Rational combination strategies to overcome resistance of GBM to checkpoint monotherapy are needed to extend the promise of immunotherapy to GBM management. Emerging evidence suggests that protein phosphatase 2A (PP2A) plays a critical role in the signal transduction pathways of both adaptive and innate immune cells and that inhibition of PP2A could enhance cancer immunity. We investigated the use of a PP2A inhibitor, LB-100, to enhance antitumor efficacy of PD1 blockade in a syngeneic glioma model.
Methods:
C57BL/6 mice were implanted with murine glioma cell line GL261-luc or GL261-WT and randomized into 4 treatment arms: (i) control, (ii) LB-100, (iii) PD1 blockade and (iv) combination. Survival was assessed and detailed profiling of tumor infiltrating leukocytes was performed.
Results:
Dual PP2A and PD1 blockade significantly improved survival compared with monotherapy alone. Combination therapy resulted in complete regression of tumors in about 25% of mice. This effect was dependent on CD4 and CD8 T cells and cured mice established antigen-specific secondary protective immunity. Analysis of tumor lymphocytes demonstrated enhanced CD8 infiltration and effector function.
Conclusion:
This is the first preclinical investigation of the effect of combining PP2A inhibition with PD1 blockade for GBM. This novel combination provided effective tumor immunotherapy and long-term survival in our animal GBM model.
Insights
Combining protein phosphatase 2A (PP2A) inhibition with PD1 blockade immunotherapy significantly improved survival in a preclinical glioblastoma model. This novel combination enhanced anti-tumor immunity and led to long-term survival in some mice.
Area of Science:
- Neuro-oncology
- Immunotherapy
- Cancer Research
Background:
- Glioblastoma (GBM) has a poor prognosis despite standard treatments.
- Immune checkpoint inhibitors (ICIs) like PD1 blockade have shown limited efficacy in GBM.
- Novel combination strategies are needed to enhance immunotherapy for GBM.
Purpose of the Study:
- To investigate the potential of combining a protein phosphatase 2A (PP2A) inhibitor (LB-100) with PD1 blockade to enhance anti-tumor immunity in a syngeneic glioma model.
- To assess the efficacy of this combination therapy in improving survival and immune responses against GBM.
Main Methods:
- C57BL/6 mice bearing GL261 glioma cells were randomized into four groups: control, LB-100, PD1 blockade, or combination therapy.
- Survival rates were monitored, and tumor-infiltrating leukocytes were analyzed for immune cell profiles and function.
Main Results:
- Combination therapy significantly improved survival compared to monotherapy.
- Approximately 25% of mice in the combination group achieved complete tumor regression.
- This response was dependent on CD4 and CD8 T cells, leading to antigen-specific protective immunity and enhanced CD8+ T cell infiltration and effector function.
Conclusions:
- This study presents the first preclinical investigation of combining PP2A inhibition with PD1 blockade for GBM.
- This novel combination demonstrates effective tumor immunotherapy and induces long-term survival in a murine GBM model.
- The findings support further investigation of this combination strategy for GBM treatment.
