S100A9-CXCL12 activation in BRCA1-mutant breast cancer promotes an immunosuppressive microenvironment associated with resistance to immunotherapy

Jianjie Li, Xiaodong Shu, Jun Xu, Sek Man Su, Un In Chan, Lihua Mo, Jianlin Liu, Xin Zhang, Ragini Adhav, Qiang Chen, Yuqing Wang, Tingting An, Xu Zhang, Xueying Lyu, Xiaoling Li, Josh Haipeng Lei, Kai Miao, Heng Sun, Fuqiang Xing, Aiping Zhang, Chuxia Deng () and Xiaoling Xu ()
Additional contact information
Jianjie Li: University of Macau
Xiaodong Shu: University of Macau
Jun Xu: University of Macau
Sek Man Su: University of Macau
Un In Chan: University of Macau
Lihua Mo: University of Macau
Jianlin Liu: University of Macau
Xin Zhang: University of Macau
Ragini Adhav: University of Macau
Qiang Chen: University of Macau
Yuqing Wang: University of Macau
Tingting An: University of Macau
Xu Zhang: University of Macau
Xueying Lyu: University of Macau
Xiaoling Li: University of Macau
Josh Haipeng Lei: University of Macau
Kai Miao: University of Macau
Heng Sun: University of Macau
Fuqiang Xing: University of Macau
Aiping Zhang: University of Macau
Chuxia Deng: University of Macau
Xiaoling Xu: University of Macau

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Immune checkpoint blockade (ICB) is a powerful approach for cancer therapy although good responses are only observed in a fraction of cancer patients. Breast cancers caused by deficiency of breast cancer-associated gene 1 (BRCA1) do not have an improved response to the treatment. To investigate this, here we analyze BRCA1 mutant mammary tissues and tumors derived from both BRCA1 mutant mouse models and human xenograft models to identify intrinsic determinants governing tumor progression and ICB responses. We show that BRCA1 deficiency activates S100A9-CXCL12 signaling for cancer progression and triggers the expansion and accumulation of myeloid-derived suppressor cells (MDSCs), creating a tumor-permissive microenvironment and rendering cancers insensitive to ICB. These oncogenic actions can be effectively suppressed by the combinatory treatment of inhibitors for S100A9-CXCL12 signaling with αPD-1 antibody. This study provides a selective strategy for effective immunotherapy in patients with elevated S100A9 and/or CXCL12 protein levels.

Date: 2022
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DOI: 10.1038/s41467-022-29151-5

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