Insights into the regulation of brain metastasis by natural killer cells using single-cell RNA sequencing and imaging mass cytometry

Abstract

Abstract Metastatic brain tumors are incurable, rapidly fatal, and five times more common than primary glial or meningeal tumors of the central nervous system (CNS). Natural Killer (NK) cells are cytotoxic lymphocytes with strong in vivo anti-tumor activity, a native ability to cross the blood-brain barrier (BBB), and a demonstrated role in the regulation of metastasis in peripheral organs. NK cells perform critical roles in anti-tumor immunosurveillance via the expression of germline-encoded activation and inhibition receptors on the cell membrane. These receptors recognize ligands on both normal and transformed cells, and ultimately determine whether an NK cell will be stimulated to kill a neoplastic cell or inhibited from killing a healthy cell. Notably, NK cells are under investigation in clinical trials as both drug targets and adoptive cell therapies. We are working to characterize NK cell-mediated regulation of brain metastasis, which appears to be dysfunctional relative to the robust NK cell anti-metastatic activity observed in peripheral tissues. We seek to elucidate a molecular mechanism for this NK cell dysfunction using in vivo models of brain metastasis in conjunction with flow cytometry, single-cell RNA sequencing (scRNA-seq), and imaging mass cytometry (IMC). An improved understanding of the functional status and transcriptional programs of NK cells in brain metastasis will inform the development of neuroprotective anti-metastatic therapies aimed at modulating and potentiating the anti-tumor action of both native and adoptively-transferred NK cells. Supported by grants from the National Cancer Institute (R01CA237376-01A1), the UCI Stem Cell Research Center, and the UCI Medical Scientist Training Program