The loss of B7-H4 expression in breast cancer cells escaping from T cell cytotoxicity contributes to epithelial-to-mesenchymal transition

Linlin Zhou; Jichun Wu; Mei Ruan; Yonglei Xiao; Hailin Lan; Qiongwen Wu; Chen-Wei Yu; Qiuyu Zhang

doi:10.1186/s13058-023-01721-5

The loss of B7-H4 expression in breast cancer cells escaping from T cell cytotoxicity contributes to epithelial-to-mesenchymal transition

Breast Cancer Res. 2023 Oct 4;25(1):115. doi: 10.1186/s13058-023-01721-5.

Authors

Linlin Zhou^{1

2}, Jichun Wu^{1

2}, Mei Ruan¹, Yonglei Xiao¹, Hailin Lan^{1

2}, Qiongwen Wu¹, Chen-Wei Yu^{3

4

5}, Qiuyu Zhang^{6

7}

Affiliations

¹ Institute of Immunotherapy, Fujian Medical University, Fuzhou, China.
² School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
³ Institute of Immunotherapy, Fujian Medical University, Fuzhou, China. dcwyu@email.nchu.edu.tw.
⁴ School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. dcwyu@email.nchu.edu.tw.
⁵ Department of Statistics and Information Science, Fu Jen Catholic University, New Taipei City, Taiwan. dcwyu@email.nchu.edu.tw.
⁶ Institute of Immunotherapy, Fujian Medical University, Fuzhou, China. qiuyu.zhang@fjmu.edu.cn.
⁷ School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. qiuyu.zhang@fjmu.edu.cn.

Abstract

Background: B7 homology 4 (B7-H4), a potential target for cancer therapy, has been demonstrated to inhibit T cell cytotoxicity in the early stages of breast cancer. However, B7-H4 manipulating breast tumor immune microenvironment (TIME) in the tumor progression remains unknown.

Methods: We engineered T cells with B7-H4-specific chimeric antigen receptors (CARs) and performed a T cell co-culture assay to characterize B7-H4 expression level in breast cancer cells escaping from T cell cytotoxicity. We generated B7-H4 knockout (KO) and overexpression (OE) breast cancer cells to determine the epithelial-to-mesenchymal transition (EMT) and stemness characteristics in vitro and in vivo, including tumor proliferation, migration, metastasis and chemoresistance. The Cancer Genome Atlas breast cancer database was accessed to investigate the correlation between B7-H4 expression levels and EMT characteristics in patients with breast cancer.

Results: Our result found that B7-H4 expression level was significantly reduced in a subset of breast cancer cells that escaped from the cytotoxicity of B7-H4 CAR-T cells. Compared with wild type cells, B7-H4 KO cells prompt EMT and stemness characteristics, including migration, invasion and metastasis, and OE cells vice versa. The increase in H3K27me3 in KO cells confirmed the epigenetic reprogramming of cancer stem cells. The IC50 of doxorubicin or oxaliplatin significantly increased in KO cells, which was in agreement with a decrease in OE cells. Moreover, a trend of downregulated B7-H4 from stage I to stage II breast cancer patients indicates that the low-expressing B7-H4 breast cancer cells escaping from TIME have spread to nearby breast lymph nodes in the cancer progression.

Conclusions: Our study illuminates the novel role of renouncing B7-H4 in breast cancer cells through immune escape, which contributes to EMT processes and provides new insights for breast cancer treatments.

Keywords: B7-H4; Breast cancer; EMT; Stemness; T cell cytotoxicity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms* / genetics
Breast Neoplasms* / pathology
Female
Humans
T-Lymphocytes*
Tumor Microenvironment / genetics