Aaditya Khatri, Courtney M McKernan, Amanda E D Van Swearingen, Vaibhav Jain, Hannah L Thrash, Arianna Towne, Jing Jin Gu, Simon G Gregory, Carey K Anders, Ann Marie Pendergast
Despite advances in treatment approaches, the mean survival for patients with brain metastases remains poor. The incidence of brain metastases continues to rise, and there remains a need to identify novel therapeutics targeting mechanisms critical for brain metastasis. We employed a multi-omic approach, including single nuclei and spatially resolved transcriptomic profiling across 23 brain metastatic samples, with the representation of lung, breast, and melanoma metastases, to identify tumor-microenvironment interactions associated with survival outcomes in brain metastasis. We found that the specific role of macrophages in disease progression is context-dependent. Activated HLA-DR+ inflammatory macrophages directly in contact with cancer cells at the tumor boundary are associated with responsiveness to therapies and improved patient survival. Conversely, reprogrammed macrophages expressing extracellular matrix proteins and TGFβ1 are associated with poor survival. These findings identify spatially distinct tumor cell-macrophage interactions associated with survival outcomes in patients with brain metastases and represent targets for immunotherapy strategies.