BRCA1 Insufficiency Induces a Hypersialylated Acidic Tumor Microenvironment That Promotes Metastasis and Immunotherapy Resistance.

Abstract

Cancer metastasis is an extremely complex process affected by many factors. An acidic microenvironment can drive cancer cell migration toward blood vessels while also hampering immune cell activity. Here, we identified a mechanism mediated by sialyltransferases that induces an acidic tumor-permissive microenvironment (ATPME) in BRCA1-mutant and most BRCA1-low breast cancers. Hypersialylation mediated by ST8SIA4 perturbed the mammary epithelial bilayer structure and generated an ATPME and immunosuppressive microenvironment with increased PD-L1 and PD1 expressions. Mechanistically, BRCA1 deficiency increased expression of VEGFA and IL6 to activate TGFβ-ST8SIA4 signaling. High levels of ST8SIA4 led to accumulation of polysialic acid (PSA) on mammary epithelial membranes that facilitated escape of cancer cells from immunosurveillance, promoting metastasis and resistance to αPD1 treatment. The sialyltransferase inhibitor 3Fax-Peracetyl Neu5Ac neutralized the ATPME, sensitized cancers to immune checkpoint blockade by activating CD8 T cells, and inhibited tumor growth and metastasis. Together, these findings identify a potential therapeutic option for cancers with a high level of PSA.

SIGNIFICANCE:

BRCA1 deficiency generates an acidic microenvironment to promote cancer metastasis and immunotherapy resistance that can be reversed using a sialyltransferase inhibitor.

• Authors: Xiaodong Shu, Jianjie Li, Un In Chan, Sek Man Su, Changxiang Shi, Xin Zhang, Tingting An, Jun Xu, Lihua Mo, Jianlin Liu, Yuqing Wang, Xiaoling Li, Min Deng, Josh Haipeng Lei, Chunfei Wang, Hao Tian, Sun Heng, Joong Sup Shim, Xuanjun Zhang, Yunlu Dai, Zhicheng Yao, Xiaying Kuang, Ying Lin, Chu-Xia Deng, Xiaoling Xu
• Journal: Cancer research (Cancer Res) Vol. 83 Issue 15 Pg. 2614-2633 (08 01 2023) ISSN: 1538-7445 [Electronic] United States
• PMID: 37227919 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2023 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Sialyltransferases
• BRCA1 protein, human
• BRCA1 Protein

Topics

• Humans
• Female
• Tumor Microenvironment
• Immunotherapy
• Breast (pathology)
• Breast Neoplasms (genetics, therapy, pathology)
• Sialyltransferases (genetics)
• Cell Line, Tumor
• BRCA1 Protein (genetics)