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Identification of Epinastine as CD96/PVR inhibitor for cancer immunotherapy
Xiangrui Zhang1, Lihan Zhang2, Beibei Li1
1School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
Background:
Poliovirus receptor (PVR) and its receptor system, including TIGIT, CD226, and CD96, play a pivotal role in orchestrating tumor immune evasion. Upon engagement with PVR on tumor cells, CD96 exerts inhibitory effects on the function of T cells and NK cells, thereby fostering tumor immune evasion. Therefore, screening of immune checkpoint inhibitors (ICIs) targeting the CD96/PVR pathway will provide promising candidates for tumor immunotherapy.
Results:
In this investigation, we employed MOE software to conduct virtual screening of small molecules from the FDA-approved drug library. Our results demonstrated that Epinastine exhibited high affinity for CD96, thereby effectively disrupting the interaction between CD96 and PVR. In vitro co-culture experiments further revealed that Epinastine effectively restored the ability of Jurkat cells to secrete IL-2. In the MC38 tumor-bearing model, Epinastine significantly enhanced the infiltration of T cells and NK cells into the tumor site and augmented their secretion of IFN-γ, leading to effective suppression of tumor growth.
Conclusions:
Our results demonstrated that the development of small molecule inhibitor Epinastine targeting CD96/PVR pathway, which proposed a promising strategy and drug candidate for cancer immunotherapy.
Insights
Epinastine, a small molecule inhibitor, disrupts the CD96/PVR pathway, enhancing anti-tumor immunity. This drug candidate shows promise for cancer immunotherapy by restoring T cell function and suppressing tumor growth.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- The poliovirus receptor (PVR) and its associated proteins (TIGIT, CD226, CD96) are crucial in tumor immune evasion.
- CD96 binding to PVR inhibits T cell and NK cell activity, promoting tumor immune evasion.
- Targeting the CD96/PVR pathway with immune checkpoint inhibitors (ICIs) offers a potential strategy for cancer immunotherapy.
Purpose of the Study:
- To identify small molecule inhibitors targeting the CD96/PVR pathway for cancer immunotherapy.
- To evaluate the efficacy of Epinastine in disrupting the CD96/PVR interaction and restoring anti-tumor immune responses.
Main Methods:
- Virtual screening of FDA-approved drugs using MOE software to identify compounds with high affinity for CD96.
- In vitro co-culture experiments to assess Epinastine's effect on IL-2 secretion in Jurkat cells.
- In vivo studies using a MC38 tumor-bearing mouse model to evaluate Epinastine's impact on immune cell infiltration and tumor growth.
Main Results:
- Epinastine demonstrated high affinity for CD96, effectively blocking the CD96/PVR interaction.
- Epinastine treatment restored IL-2 secretion in Jurkat cells.
- In vivo, Epinastine enhanced T cell and NK cell infiltration into tumors, increased IFN-γ secretion, and suppressed tumor growth.
Conclusions:
- Epinastine is a promising small molecule inhibitor targeting the CD96/PVR pathway.
- Epinastine represents a potential drug candidate for cancer immunotherapy.
- The study highlights the therapeutic potential of targeting the CD96/PVR axis.
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