Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer

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. We investigated the role of cancer-associated fibroblasts (CAFs) and immune cells in mediating resistance to chemotherapy and lung metastatic relapse in models of triple negative breast cancer. Chemotherapy, routinely used to treat breast cancer, induces extensive tissue damage, eliciting an inflammatory response that may hinder efficacy and promote metastatic relapse. 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. 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.