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

Breast Cancer. 2023 Nov;30(6):1041-1053. doi: 10.1007/s12282-023-01498-7. Epub 2023 Aug 29.

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.

Keywords: Breast cancer; Immune checkpoint inhibitors; Immune checkpoint molecules; Triple-negative breast cancer; Tumor-infiltrating lymphocytes.

MeSH terms

  • B7-H1 Antigen* / metabolism
  • Biomarkers, Tumor / metabolism
  • Humans
  • Lymphocytes, Tumor-Infiltrating
  • Prognosis
  • Receptors, Androgen / metabolism
  • Triple Negative Breast Neoplasms* / pathology
  • Tumor Microenvironment

Substances

  • B7-H1 Antigen
  • Receptors, Androgen
  • Biomarkers, Tumor