Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer [RNA-seq]

Mortality from breast cancer is almost exclusively a result of tumor metastasis and resistance to therapy and therefore understanding the underlying mechanisms is an urgent challenge. Chemotherapy, routinely used to treat breast cancer, induces extensive tissue damage, eliciting an inflammatory response that may hinder efficacy and promote metastatic relapse. Here we show that systemic treatment with chemotherapy following resection of a triple-negative breast tumor induced the expression of complement factors in lung fibroblasts and modulated an immunosuppressive metastatic niche that supported lung metastasis. CAF-derived complement signaling mediated the recruitment of myeloid-derived suppressor cells (MDSCs) to the metastatic niche, thus promoting T cell dysfunction. Functionally, we show that pharmacological targeting of complement signaling in combination with chemotherapy alleviated immune dysregulation and attenuated lung metastasis. Our findings suggest that combining cytotoxic treatment with blockade of complement signaling in triple-negative breast cancer patients may attenuate the adverse effects of chemotherapy, thus offering a promising approach for clinical use. Comparative gene expression profiling analysis of RNA-seq data for fibroblasts isolated from early stage metastatic lungs of mice treated with doxorubicin (Dox n=5) or saline as control (Pbs, n=4).