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Anti-angiogenesis therapy overcomes the innate resistance to PD-1/PD-L1 blockade in VEGFA-overexpressed mouse tumor models

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Abstract

The effectual clinical benefits of immune checkpoint inhibitor (ICI) are hampered by a high rate of innate resistance, and VEGFA may contribute to ICI treatment resistance. In this study, we endeavored to assess the tumor microenvironment (TME) in VEGFA-overexpressed human tumors and mouse tumor models, and to explore whether anti-angiogenesis therapy can overcome the innate resistance to ICI in hyperangiogenesis mouse tumor models and the underlying mechanism. Effect of VEGFA on clinical prognosis and TME was analyzed using TCGA data. The VEGFA-overexpressed mouse breast and colon subcutaneous models were established. PD-1 mAb or apatinib alone and combination therapy were used. Immunohistochemistry and immunofluorescence were used to assess angiogenesis and hypoxia. Flow cytometry, RNA sequencing and MCP-counter were applied to detect tumor immunomicroenvironment. High level of VEGFA mRNA in human tumors is related to poor prognosis and hypoxic, angiogenic and immunosuppressive TME. Upregulation of VEGFA increased the degree of malignancy of tumor cells in vitro and in vivo. VEGFA-overexpressed models were characterized by hypoxic, hyperangiogenic and immunosuppressive TME and indicated innate resistance to ICI. In tumor-bearing mice without VEGFA overexpression, the combination therapy had no synergistic anti-tumor effect compared to monotherapy. However, apatinib alleviated hyperangiogenesis and hypoxia in TME and converted the immunosuppressive TME into an immunostimulatory one in VEGFA-overexpressed tumors. Thus, anti-angiogenesis therapy could improve the efficiency of ICI in VEGFA-overexpressed tumors. Revealing whether there is hypervascularization in tumor tissues may help to clarify the adoption of anti-angiogenesis and ICI combination therapy or ICI monotherapy in cancer treatment.

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Abbreviations

AA:

Anti-angiogenesis

GSEA:

Gene set enrichment analysis

ICI:

Immune checkpoint inhibitor

ICER:

Incremental cost-effectiveness ratio

IPRES:

Innate anti-PD-1 resistance

KI:

Tyrosine kinase inhibitor

LAG-3:

Lymphocyte activation gene-3

MDSCs:

Myeloid-derived suppressor cells

MVD:

Microvascular density

ORR:

Objective response rates

OS:

Overall survival

PD-1:

Programmed cell death 1

PD-L1:

Programmed cell death ligand 1

QALY:

Quality-adjusted life-year

RCC:

Renal cell carcinoma

TCGA:

The Cancer Genome Atlas database

TIGIT:

T cell immunoreceptor with Ig and ITIM domain

TILs:

Tumor-infiltrating lymphocytes

TIM-3:

T cell immunoglobulin and mucin-domain containing-3

TME:

Tumor microenvironment

TOX:

Thymocyte selection-associated HMG box protein

Tregs:

T regulatory cells

TRAE:

Treatment-related adverse effect

UCSC:

University of California Santa Cruz database

VEGFA:

Vascular endothelial growth factor A

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Acknowledgements

We gratefully thank the Natural Science Foundation of China and School of Medicine, Shanghai Jiaotong University, for the funding.

Funding

This work is supported by grants from National Natural Science Foundation of China (81472843 to W. X.) and the study program of clinical capacity in urgently needed postgraduate majors in the School of Medicine, Shanghai Jiaotong University (JQ201703).

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Author notes

  1. Qiaohong Wang and Jingze Gao are contribution equally to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, School of Medicine, Renji Hospital, Shanghai Jiaotong University, Shanghai, 200127, People’s Republic of China

    Qiaohong Wang, Jingze Gao, Wen Di & Xia Wu

  2. Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, People’s Republic of China

    Qiaohong Wang, Jingze Gao, Wen Di & Xia Wu

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  3. Wen Di
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  4. Xia Wu
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Contributions

XW and WD designed and supervised the study. QHW performed the experiments in vitro. QHW and JZG established the animal model and conducted the animal study. JZG was responsible for the TCGA and mRNA sequencing analysis. QHW and XW completed the manuscript. All authors read and approved the final manuscript.

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Correspondence to Xia Wu.

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The authors declare that they have no competing interests.

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We state that animal experiment in our study was approved by the Institutional Animal Care and Use Committee of Shanghai Jiao Tong University.

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Wang, Q., Gao, J., Di, W. et al. Anti-angiogenesis therapy overcomes the innate resistance to PD-1/PD-L1 blockade in VEGFA-overexpressed mouse tumor models. Cancer Immunol Immunother 69, 1781–1799 (2020). https://doi.org/10.1007/s00262-020-02576-x

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