Abstract
Background
Many anti-angiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy. Anlotinib has demonstrated anti-tumor efficacy in non-small cell lung cancer (NSCLC) in third-line clinical trials. However, its roles in immune regulation and potentially synergistic anti-tumor effect in combination with immune checkpoint inhibition remain unclear.
Methods
Here, based on a syngeneic lung cancer mouse model, the intratumoral immunological changes post-anlotinib treatment in the model were assessed. Furthermore, it was tested whether anlotinib could enhance the anti-tumor effect of αPD-1 in vivo.
Results
This study shows that anlotinib increased infiltration of the innate immune cells, including natural killer (NK) cells, and antigen-presenting cells (APC), which include M1-like tumor-associated macrophages (TAM) and dendritic cells (DC), whereas the percentage of M2-like TAM was dramatically reduced. Subsequently, when combined with PD-1/PD-L1 (programmed cell death 1/PD-1 ligand 1) blockade, anlotinib conferred significantly synergistic therapeutic benefits.
Conclusions
Overall, these findings describe a role for anlotinib in the innate immune cells in the tumor microenvironment and a potentially synergistic anti-tumor combination with immune checkpoint inhibition.
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Abbreviations
- APC:
-
Antigen-presenting cells
- DCs:
-
Dendritic cells
- ICB:
-
Immune checkpoint blockade
- IHC:
-
Immunohistochemistry
- MDSC:
-
Myeloid-derived suppressor cells
- TAM:
-
Tumor-associated macrophage
- TIME:
-
Tumor immune microenvironment
- TKI:
-
Tyrosine kinase receptor inhibitor
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Funding
This work was supported in part by grants from the National Natural Science Foundation of China (No. 81703786 and No. 81803914) and from the Tian** Science and Technology Committee (No. 18JCZDJC36700).
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YY designed, performed, and analyzed the experiments, and wrote the manuscript. LL, ZJ, and BW performed the experiments. YY, ZJ, and ZP provided the reagents and technical support. ZP designed and edited the manuscript. All the authors were involved in critical revision of the final manuscript.
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All procedures involving animals were performed according to the Ethics Committee of Tian** Medical University (Tian**, China).
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Female C57BL/6 mice (6–8 weeks old) were purchased from Bei**g HFK Bioscience (Bei**g, China).
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LLC (Lewis) murine lung carcinoma cells were purchased via the National Cancer Institute cell bank repository of China, and the cell line was authenticated there. Further, before use, the cell line tested negative for mycoplasma via the Mycoplasma ELISA Kit from Invitrogen (Carlsbad, CA, USA).
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Yang, Y., Li, L., Jiang, Z. et al. Anlotinib optimizes anti-tumor innate immunity to potentiate the therapeutic effect of PD-1 blockade in lung cancer. Cancer Immunol Immunother 69, 2523–2532 (2020). https://doi.org/10.1007/s00262-020-02641-5
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DOI: https://doi.org/10.1007/s00262-020-02641-5