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Immunohistological analysis of B7-H4, IDO1, and PD-L1 expression and tumor immune microenvironment based on triple-negative breast cancer subtypes

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Abstract

Background

B7 homolog 4 (B7-H4) and indoleamine 2,3-dioxygenase (IDO1) are factors involved in the inhibition of antitumor activity and are new therapeutic targets for immune checkpoint therapy. Our study aimed to simultaneously investigate the interrelationship among B7-H4, IDO1 and programmed cell death ligand 1 (PD-L1) expression in triple-negative breast cancer (TNBC), including tumor immune microenvironment (TIME) and TNBC subtypes.

Methods

Immunostaining for PD-L1, B7-H4, and IDO1 was performed on whole-slide sections of 119 cases of TNBC. The TIME was evaluated based on stromal tumor infiltrating lymphocytes (sTILs; %), pattern classification of TILs, tumor–stroma ratio (TSR), and tertiary lymphoid structure (TLS). TNBC subtypes were also determined by immunohistochemistry analysis of cytokeratin 5/6 and androgen receptor (AR) expression.

Results

B7-H4 expression was significantly higher in cases with a combined positive score cutoff of 5 for PD-L1 (clone 28–8; p = 0.021), inflamed TIL pattern (p = 0.007), and TLS ≥ 4 (p = 0.006). B7-H4 expression was higher in case of CK5/6 ≥ 10 (p = 0.035). The H-scores of AR and B7-H4 were inversely correlated (ρ = − 0.509, p < 0.001). B7-H4 and IDO1 expression levels were inversely correlated in cases with AR < 10 (ρ = − 0.354, p < 0.001).

Conclusions

These results suggest that considering the TIL pattern and TLS and identifying the expression of PD-L1 and the basal-like type are useful for estimating B7-H4 expression. In addition, luminal androgen receptor (LAR)-type is frequently deficient in B7-H4 expression. In non-LAR types, B7-H4 and IDO1 expression are exclusive.

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Data availability

The datasets that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Mrs. Kaoru Tsuboi, Mrs. Megumi Kuriyama, and Mr. Nobuhisa Iwachidou for their technical assistance.

Funding

This work was supported by JSPS KAKENHI (Grant number 21K06934) and Research Project Grants from Kawasaki Medical School (R04G002).

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Authors and Affiliations

  1. Department of Pathology, Kawasaki Medical School, 577 Matsushima, Kurashiki, 701-0192, Japan

    Fumiaki Sanuki, Yuka Mikami, Hirotake Nishimura, Yoshinori Fujita & Takuya Moriya

  2. Department of Pathology, Kawasaki Medical School General Medical Center, Okayama, Japan

    Yasumasa Monobe

  3. Department of Breast and Thyroid Surgery, Kawasaki Medical School, Kurashiki, Japan

    Tsunehisa Nomura & Naruto Taira

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  1. Fumiaki Sanuki
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Contributions

This study was designed and conceived by FS and TM. The material was prepared by Yuka- M, YF, and FS. Data collection and statistical analysis were performed by FS. The stained specimens were evaluated by FS and TM. Technical input was provided by NH, Yuka-M, and Yasumasa-M; Clinical information was obtained by NN and NT. The first draft of the manuscript was written by FS.

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Correspondence to Takuya Moriya.

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The authors declare no conflict of interest.

Ethical approval

This study was conducted after obtaining approval from the Ethics Committee of Kawasaki Medical School and in accordance with the Declaration of Helsinki (approval number 5013–03).

Informed consent

Although this was a retrospective study, each patient provided informed consent for study inclusion before surgery. A summary of the study protocol was published on a web page, which explained the study and provided an opportunity for dissenting opinions to be expressed.

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Sanuki, F., Mikami, Y., Nishimura, H. et al. Immunohistological analysis of B7-H4, IDO1, and PD-L1 expression and tumor immune microenvironment based on triple-negative breast cancer subtypes. Breast Cancer 30, 1041–1053 (2023). https://doi.org/10.1007/s12282-023-01498-7

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