Abstract Rationale While advances in treatment approaches to lung cancer have improved overall survival in patients, the mean survival for patients with brain and pleural metastases remains 6-8 months. As such, there remains an unmet need to identify novel therapeutic strategies specifically targeting drivers of tumor growth in the metastatic microenvironment. There remain gaps in understanding the specific tumor-immune cell interactions in the metastatic microenvironment impacting tumor progression, and an understanding of the diverse immune cell populations will allow for the development of novel immunotherapy strategies. Methods We performed single cell and spatial transcriptomic profiling across 11 lung cancer brain metastases and 8 lung cancer associated malignant pleural effusions to identify important tumor-microenvironment interactions associated with survival outcomes. Analyses included differential gene expression, pathway analysis, and trajectory analysis. Protein validation was conducted via immunofluorescence staining and flow cytometry using an 11-parameter custom flow panel. Results We found a context-dependent role of macrophage reprogramming in disease progression in brain and pleural metastases. Activated HLA-DR+ inflammatory macrophages directly in contact with cancer cells are associated with responsiveness to systemic therapies and improved patient survival. Pro-tumorigenic HLA-DR-negative macrophages with upregulation of angiogenesis, TGFβ, and extra-cellular matrix protein signaling are associated with poor survival outcomes. Trajectory analysis identified precise transcriptomic changes between control macrophages and those in cancer patients with good and poor survival outcomes. Conclusions We identified distinct immune cell transcriptomic signatures in human brain and pleural metastases associated with survival outcomes. These findings offer not only promising prognostic value for patient outcomes and response to immunotherapy but also insights into novel immunotherapy targets based on specific changes in the proteomic and transcriptomic signatures. This abstract is funded by: National Institute of Health, Department of Defense, and CHEST Foundation
Khatri et al. (Fri,) studied this question.