CSF1R inhibition combined with STAT5 blockade normalized TAM phenotype and sustained tumor control.

  • Major Finding: CSF1R inhibition combined with STAT5 blockade normalized TAM phenotype and sustained tumor control.

  • Concept: CSF2–STAT5 signaling induces resistance to CSF1R inhibition in TAMs that support brain metastasis.

  • Impact: Understanding adaptive resistance mechanisms to CSF1R inhibition can guide development of TAM-targeted strategies.

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An abundant cell type in the tumor microenvironment of brain metastases is tumor-associated macrophages/microglia (TAM). These cells have been implicated in metastatic colonization and outgrowth; therefore, therapeutically targeting this population has been considered as an attractive strategy. One such strategy that has been used in targeting the TAM population are colony-stimulating factor 1 receptor (CSF1R) inhibitors, which have shown preclinical efficacy. However, questions regarding long-term efficacy of these inhibitors and potential mechanisms of adaptive resistance remain. Klemm and colleagues investigated distinct stages of brain metastasis arising from breast cancer cells in mice and found CSF1R expression in the microenvironment to mainly be restricted to immune cells, with cancer cell viability in culture being unaltered after CSF1R inhibitor treatment. Most TAMs present within the microenvironment were derived from brain-resident microglia, and CSF1R inhibition blocked the interaction between microglia and brain metastatic cells, contributing to reduced tumor cell colonization. Treatment with a CSF1R inhibitor also substantially delayed tumor onset in mice as well as prolonged median survival, but, once tumors developed, the growth rate was unchanged. Conversely, CSF1R inhibition reduced outgrowth of established brain metastases, but regrowth in these models was detected and alterations to median survival were not observed. A majority of CSF1R-expressing cells were depleted after monotherapy, but investigation into signaling pathways that protect against CSF1R inhibitor–induced cell death in those TAMs that survived revealed an overrepresentation of CSF2Rb-and STAT5-associated pathways, suggesting their compensatory induction post-CSF1R blockade. Indeed, dual targeting of CSF1R and CSF2Rb–STAT5 by either a CSF2 antibody or a STAT5 inhibitor enhanced the antitumor response both in vitro and in vivo as well as altered TAM morphology, indicating a return to a more normal phenotype. This study shows that CSF1R inhibition to target TAMs can reduce onset of brain metastases, but the induction of CSF2–STAT5 signaling provides adaptive resistance to this inhibition. Dual targeting of these pathways may therefore be necessary to provide clinical benefit to patients with brain metastasis.

Klemm F, Möckl A, Salamero-Boix A, Alekseeva T, Schäffer A, Schulz M, et al. Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis. Nat Cancer 2021;2:1086–101.

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