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

Lea Monteran, Nour Ershaid, Hila Doron, Yael Zait, Ye’ela Scharff, Shahar Ben-Yosef, Camila Avivi, Iris Barshack, Amir Sonnenblick and Neta Erez ()
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Lea Monteran: Tel Aviv University
Nour Ershaid: Tel Aviv University
Hila Doron: Tel Aviv University
Yael Zait: Tel Aviv University
Ye’ela Scharff: Tel Aviv University
Shahar Ben-Yosef: Tel Aviv University
Camila Avivi: Sheba Medical Center
Iris Barshack: Sheba Medical Center
Amir Sonnenblick: Tel Aviv University
Neta Erez: Tel Aviv University

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

Abstract: Abstract 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 doxorubicin, but not cisplatin, following resection of a triple-negative breast tumor induces the expression of complement factors in lung fibroblasts and modulates an immunosuppressive metastatic niche that supports lung metastasis. Complement signaling derived from cancer-associated fibroblasts (CAFs) mediates 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 alleviates immune dysregulation and attenuates 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.

Date: 2022
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DOI: 10.1038/s41467-022-33598-x

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