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

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 alpha PD-1 antibody. This study provides a selective strategy for effective immunotherapy in patients with elevated S100A9 and/or CXCL12 protein levels. Defects in BRCA1, a gene involved in homologous recombination DNA repair, are common in triple negative breast cancer. Here the authors show that Brca1 deficiency in preclinical breast cancer models is associated with the accumulation of myeloid derived suppressive cells and resistance to immune checkpoint blockade, that could be overcome by targeting S100A9 and CXCL12.

Automated summary

This study explores the mechanism behind the poor response to immune checkpoint blockade in breast cancers caused by BRCA1 deficiency. The authors identify the activation of S100A9-CXCL12 signaling and the accumulation of myeloid-derived suppressor cells as contributing factors. They also demonstrate that the combination of inhibitors targeting S100A9-CXCL12 signaling and alpha PD-1 antibody can effectively suppress the oncogenic actions and improve immunotherapy response.