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PD-L1 antibody enhanced β-glucan antitumor effects via blockade of the immune checkpoints in a melanoma model

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Abstract

In the tumor microenvironment (TME), one of the major functions of tumor-recruited CD11b+ cells are the suppression of the T-cell-mediated anti-tumor immune response. β-glucan could convert the phenotype of tumor-recruited CD11b+ cells from the suppressive to the promotive, and enhanced their anti-tumor effects. However, β-glucan could enhance the PD-1/PD-L1 expression on CD11b+ cells, while PD-1 could inhibit macrophage phagocytosis and PD-L1 could induce a co-inhibitory signal in T-cells and lead to T-cell apoptosis and anergy. These protumor effects may be reversed by PD-1/PD-L1 block therapy. In the present study, we focused on the efficacy of β-glucan anti-tumor therapy combined with anti-PD-L1 mAb treatment, and the mechanism of their synergistic effects could be fully verified. We verified the effect of β-glucan (i.e., inflammatory cytokine secretion of TNF-α, IL-12, IL-6, IL-1β and the expression of immune checkpoint PD-1/PD-L1) in naïve mouse peritoneal exudate CD11b+ cells. In our mouse melanoma model, treatment with a PD-L1 blocking antibody with β-glucan synergized tumor regression. After treatment with β-glucan and anti-PD-L1 mAb antibody, tumor infiltrating leukocyte (TILs) not only showed a competent T-cell function (CD107a, perforin, IL-2, IFN-γ and Ki67) and CTL population, but also showed enhanced tumor-recruited CD11b+ cell activity (IL-12, IL-6, IL-1β and PD-1). This effect was also verified in the peritoneal exudate CD11b+ cells of tumor-bearing mice. PD-1/PD-L1 blockade therapy enhanced the β-glucan antitumor effects via the blockade of tumor-recruited CD11b+ cell immune checkpoints in the melanoma model.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AP-BG:

Aureobasidium pullulans-Produced β-glucan

CTLs:

Cytotoxic T-cells

MDSC:

Myeloid-derived suppressor cells

MFI:

Mean fluorescence intensity

PECs:

Peritoneal exudate cells

PMA:

Phorbol 12-myristate 13-acetate

TADC:

Tumor-associated DCs

TAM:

Tumor-associated macrophages

TGI:

Tumor growth inhibition

TIL:

Tumor-infiltrating leukocytes

TIM:

Tumor-infiltrating myeloid cells

TME:

Tumor microenvironment

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Acknowledgements

The authors are grateful to thank Ms. Y Sato for her invaluable technical assistance.

Funding

This study was supported by research grants from the Grants of Ministry of Education, Culture, Sports, Science and Technology of Japan (Grants-in-Aid 18K08558, 21K15586, 21K08634); grants from the National Center for Child Health and Development (2021C-40, 29-09).

Author information

Author notes

  1. Masayuki Fu**o and **ao-Kang Li contributed equally.

Authors and Affiliations

  1. Division of Transplantation Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan

    **n Hu, Yifang Shui, Hiroshi Hirano, Masayuki Fu**o & **ao-Kang Li

  2. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Yifang Shui, Wen-Zhi Guo & **ao-Kang Li

  3. Aureo Co., Ltd., Chiba, Japan

    Kisato Kusano

  4. Laboratory Animal, and Pathogen Bank, Management Department of Biosafety, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan

    Masayuki Fu**o

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  3. Hiroshi Hirano
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  7. **ao-Kang Li
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Contributions

XH, YFS, HH, MF, KK, WZG and XKL and conceived and designed the project; XH and YFS acquired the data; HH, MF, KK, WZG and XKL analyzed and interpreted the data; XH, YFS and XKL wrote the paper. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Masayuki Fu**o or **ao-Kang Li.

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KK is an employee of Aureo Co., Ltd.

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Mice were cared for in accordance with the National Research Institute for Child Health and Development (NCCHD) guidelines (A2017-005-C03) on laboratory animal welfare.

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Hu, X., Shui, Y., Hirano, H. et al. PD-L1 antibody enhanced β-glucan antitumor effects via blockade of the immune checkpoints in a melanoma model. Cancer Immunol Immunother 72, 719–731 (2023). https://doi.org/10.1007/s00262-022-03276-4

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