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Immune-Mediated Antitumor Effect By VEGFR2 Selective Inhibitor For Gastric Cancer
Ju Yang1, Jing Yan1, Jie Shao1
1The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing 210008, People's Republic of China.
Background:
It was previously reported that targeting vascular epithelial growth factor (VEGF)/VEGFR could modulate the antitumor immunity. VEGFR2 inhibitor YN968D1 is a highly selective VEGFR2 inhibitor and was approved for the treatment of late-stage gastric cancer in 2014, but its role in antitumor immunity remains unknown.
Materials And Methods:
In this study, we investigated the effects of YN968D1 on the function of T cells in vitro by testing the cytotoxicity and cytokine production. Next, we constructed peritoneal dissemination and subcutaneous gastric cancer mouse model to assess the cytotoxicity of YN968D1-treated T cells in vivo, respectively.
Results:
We found that the use of YN968D1 in CD8+ T cells could reduce the expression levels of inhibitory checkpoints, such as Lag-3, PD-1, and Tim3, escalate the production of IFN-γ and IL-2 and promote the cytotoxicity of T cells dramatically in vitro. The transfer of YN968D1-treated T cells achieved better tumor control compared to DMSO-treated T cells or control in both peritoneal dissemination and subcutaneous gastric cancer mouse models.
Conclusion:
Our results indicate that YN968D1 can enhance the T cell-mediated antitumor immunity.
Insights
The VEGFR2 inhibitor YN968D1 enhances T cell-mediated antitumor immunity by reducing inhibitory checkpoints and boosting T cell function. This promotes better tumor control in gastric cancer models.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Targeting vascular endothelial growth factor (VEGF)/VEGFR pathways influences antitumor immunity.
- YN968D1, a selective VEGFR2 inhibitor, is approved for late-stage gastric cancer but its immunomodulatory effects are unknown.
Purpose of the Study:
- To investigate the impact of YN968D1 on T cell function and antitumor immunity.
- To evaluate YN968D1's efficacy in preclinical gastric cancer models.
Main Methods:
- In vitro assessment of YN968D1 effects on T cell cytotoxicity and cytokine production.
- In vivo evaluation using peritoneal dissemination and subcutaneous gastric cancer mouse models.
Main Results:
- YN968D1 reduced inhibitory checkpoints (Lag-3, PD-1, Tim3) on CD8+ T cells.
- Increased IFN-γ and IL-2 production and enhanced T cell cytotoxicity in vitro.
- YN968D1-treated T cells demonstrated superior tumor control in mouse models.
Conclusions:
- YN968D1 enhances T cell-mediated antitumor immunity.
- YN968D1 shows potential as an immunomodulatory agent in cancer therapy.
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