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

## TL;DR

This study finds that BRCA1 mutations in breast cancer lead to an immunosuppressive environment that resists immunotherapy, but this resistance can be overcome by targeting S100A9 and CXCL12.

## Contribution

The study identifies S100A9-CXCL12 signaling as a novel driver of immunosuppression in BRCA1-mutant breast cancer and proposes a combinatory treatment strategy.

## Key findings

- BRCA1 deficiency activates S100A9-CXCL12 signaling, promoting tumor progression and immunosuppression.
- This signaling leads to accumulation of myeloid-derived suppressor cells, causing resistance to immunotherapy.
- Combining S100A9-CXCL12 inhibitors with αPD-1 antibody effectively suppresses these oncogenic effects.

## 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.

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.