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GSK0660 enhances antitumor immunotherapy by reducing PD-L1 expression
Bibimaryam Khan1, Mingjun Chen2, Huijie Wang2
1School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu Province, 212013, China; School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, 212013, China.
Abstract:
Blockade of PD-1/PD-L1 immune checkpoint is wildly used for multiple types of cancer treatment, while the low response rate for patients is still completely unknown. As nuclear hormone receptor, PPARδ (peroxisome-proliferator-activated receptor) regulates cell proliferation, inflammation, and tumor progression, while the effect of PPARδ on tumor immune escape is still unclear. Here we found that PPARδ antagonist GSK0660 significantly reduced colon cancer cell PD-L1 protein and gene expression. Luciferase analysis showed that GSK0660 decreased PD-L1 gene transcription activity. Moreover, reduced PD-L1 expression in colon cancer cells led to increased T cell activity. Further analysis showed that GSK0660 decreased PD-L1 expression in a PPARδ dependent manner. Implanted tumor model analysis showed that GSK0660 inhibited tumor immune escape and the combined PD-1 antibody with GSK0660 effectively enhanced colorectal cancer immunotherapy. These findings suggest that GSK0660 treatment could be an effective strategy for cancer immunotherapy.
Insights
The PPARδ antagonist GSK0660 reduces PD-L1 expression in colon cancer cells, enhancing T cell activity and improving colorectal cancer immunotherapy when combined with PD-1 blockade.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- PD-1/PD-L1 immune checkpoint blockade is a key cancer therapy, but patient response rates remain low.
- The role of peroxisome-proliferator-activated receptor delta (PPARδ) in tumor immune escape is not well understood.
- PPARδ influences cell proliferation, inflammation, and tumor progression.
Purpose of the Study:
- To investigate the effect of PPARδ on PD-L1 expression in colon cancer.
- To evaluate the potential of PPARδ antagonism as a strategy to enhance cancer immunotherapy.
Main Methods:
- Utilized GSK0660, a PPARδ antagonist, in colon cancer cell lines.
- Assessed PD-L1 protein and gene expression using various assays.
- Performed luciferase reporter assays to analyze gene transcription activity.
- Evaluated T cell activity and tumor immune escape in an implanted tumor model.
Main Results:
- GSK0660 significantly reduced PD-L1 protein and gene expression in colon cancer cells.
- GSK0660 decreased PD-L1 gene transcription activity in a PPARδ-dependent manner.
- Reduced PD-L1 expression led to increased T cell activity and inhibited tumor immune escape.
- Combination therapy of GSK0660 and PD-1 antibody enhanced colorectal cancer immunotherapy.
Conclusions:
- PPARδ antagonism, specifically with GSK0660, effectively reduces PD-L1 expression in colon cancer.
- GSK0660 shows promise in overcoming immune escape mechanisms in cancer.
- Combined GSK0660 and PD-1 blockade represents a potential strategy to improve colorectal cancer immunotherapy outcomes.
