Abstract
Purpose
Apatinib, an antiangiogenic drug, has shown beneficial effects only in a fraction of advanced gastric cancer (GC) patients. Given the recent success of immunotherapies, combination of apatinib with immune checkpoint inhibitor may provide sustained and potent antitumor responses.
Methods
Immunocompetent mice with subcutaneous MFC tumors grown were given a combination of apatinib and anti-PD-L1 antibody therapy. GC tissues from patients undergoing curative resection in China were collected, and the density of HEVs, MSI status and tumor-infiltrated lymphocytes were analyzed by immunohistochemical staining.
Results
Combined apatinib and PD-L1 blockade therapy synergistically delayed tumor growth and increased survival in MFC-bearing immunocompetent mice. The combination therapy promoted antitumor immunity by increasing the ratio of CD8+ cytotoxic T cells to Foxp3+ Treg cells, the accumulation of CD20+ B cells and the Th1/Th2 cytokine ratio (IFN-γ/IL-10). The combination therapy induced the formation of HEVs through activation of LTβR signaling, thus promoting CD8+ cytotoxic T cell and CD20+ B cell infiltration in tumors. In clinical GC samples, the density of HEVs positively correlated with the intratumoral infiltration of CD8+ cytotoxic T cells and CD20+ B cells. MSI-high GC showed a higher density of HEVs, CD8+ cytotoxic T cells and CD20+ B cells than MSS/MSI-low GC. GC patients with high densities of HEVs, CD8+ cytotoxic T cells and CD20+ B cells had an improved prognosis with superior overall survival.
Conclusion
Combining apatinib with PD-L1 blockade treatment synergistically enhances antitumor immune responses and promotes HEV formation in GC.
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Data availability
The datasets supporting the conclusions of this article are included within the article and its additional files.
Abbreviations
- GC:
-
Gastric cancer
- HEVs:
-
High endothelial venules
- MSI:
-
Microsatellite instability
- MSS:
-
Microsatellite stable
- PD-L1:
-
Programmed death ligand 1
- VEGFR2:
-
Vascular endothelial growth factor receptor 2
- OS:
-
Overall survival
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Acknowledgements
This work was supported by the following: National Natural Science Foundation of China (81902392); Clinical Research Plan of SHDC (No. SHDC2020CR3033B); Shanghai Committee of Science and Technology (18140900502).
Funding
This work was supported by the following: National Natural Science Foundation of China (81902392); Clinical Research Plan of SHDC (No. SHDC2020CR3033B); Shanghai Committee of Science and Technology (18140900502).
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YZ, HRS, FW performed the experiments; YZ analyzed the data and prepared the manuscript; YZ, JPG, YKH and HH provided the samples; HRS, FW, JPG and YKH aided the data analysis. YZ and HH wrote the paper; HRS and FW commented on the study and revised the paper; HH supervised the project; YZ and HH designed the research. All authors discussed the results and commented on the manuscript.
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The study was approved by the ethics committee of the Fudan University Shanghai Cancer Center and signed informed consent was obtained from each patient. All animal procedures were performed according to national guidelines and approved by the Institutional Committee of Fudan University for Animal Research.
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Zhang, Y., Wang, F., Sun, Hr. et al. Apatinib combined with PD-L1 blockade synergistically enhances antitumor immune responses and promotes HEV formation in gastric cancer. J Cancer Res Clin Oncol 147, 2209–2222 (2021). https://doi.org/10.1007/s00432-021-03633-3
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DOI: https://doi.org/10.1007/s00432-021-03633-3