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Anlotinib optimizes anti-tumor innate immunity to potentiate the therapeutic effect of PD-1 blockade in lung cancer

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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 Tianjin Science and Technology Committee (No. 18JCZDJC36700).

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Authors and Affiliations

  1. Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China

    Yinli Yang, Ling Li, Zhansheng Jiang, Bin Wang & Zhanyu Pan

  2. Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China

    Yinli Yang, Ling Li & Zhanyu Pan

  3. Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

    Yinli Yang & Zhansheng Jiang

  4. Tianjin’s Clinical Research Center for Cancer, Tianjin, China

    Bin Wang & Zhanyu Pan

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  1. Yinli Yang
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  2. Ling Li
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  4. Bin Wang
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Contributions

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.

Corresponding author

Correspondence to Zhanyu Pan.

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Conflict of interest

The authors declare no conflicts of interest regarding this article.

Ethical approval

All procedures involving animals were performed according to the Ethics Committee of Tianjin Medical University (Tianjin, China).

Animal source

Female C57BL/6 mice (6–8 weeks old) were purchased from Beijing HFK Bioscience (Beijing, China).

Cell line authentication

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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