Resistance undone

A study co-led by Ludwig Lausanne’s Johanna Joyce and Florian Klemm, along with Lisa Sevenich of the Georg-Speyer-Haus Institute for Tumor Biology and Experimental Therapy, in Frankfurt, identified and preclinically validated combination treatments for the typically deadly brain metastases of breast cancer. The combination therapy, reported in October in Nature Cancer, targets tumor-associated macrophages and microglia (TAMs), immune cells found within brain metastases that cancer cells can manipulate to support their growth and survival. In earlier studies, Johanna’s lab had found that inhibiting the CSF1 receptor (CSF1R), an essential signaling protein on TAMs, reprograms these cells into an anti-tumor state and significantly prolongs survival in preclinical mouse models of gliomas. The current study, in brain metastasis, shows that targeting CSF1R is initially effective but ultimately fosters an adaptive resistance mechanism in TAMs in breast-to-brain metastases. That mechanism centers on another signaling protein on TAMs, the CSF2 receptor, and a protein that helps transmit its signals, STAT5. The mechanism revives tumor growth by promoting the expression of genes involved in inflammation and wound repair. Blockade of this adaptive signaling pathway, in concert with CSF1R inhibition, reeducates TAMs into an anti-cancer state and significantly extends survival in mouse models of breast-to-brain metastases.

This article appeared in the February 2022 issue of Ludwig Link. Click here to download a PDF (1 MB).


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