A Faithful In Vivo Model Of Human Macrophages In Metastatic Melanoma

Despite recent therapeutic progress, advanced melanoma remains lethal for many patients. The composition of the immune tumor microenvironment (TME) has decisive impacts on disease outcome and therapy response. High dimensional analyses of patient samples provide insight on the composition and heterogeneity of the immune TME. Macrophages are known for their cancer-supportive role, but the underlying mechanisms are incompletely understood, and experimental in vivo systems are needed to test the functional properties of these cells. We characterize a humanized mouse model, reconstituted with a human immune system and a human melanoma, in which: (1) human macrophages support metastatic spread of the tumor; and (2) tumor-infiltrating macrophages have a specific transcriptional signature that faithfully represents the transcriptome of macrophages from patient melanoma samples and is associated with shorter survival. This model complements patient sample analyses, enabling the elucidation of fundamental principles in melanoma biology, and the development and evaluation of candidate therapies. Overall design: Immunodeficient "MISTRG" mice were repopulated with human CD34+ hematopoietic stem and progenitor cells. A human melanoma cell line (Me275) was implanted in the flank of the mice. Human CD45+ cells were isolated from tissues of 5 mice (repopulated with CD34+ cells from 2 donors) and pooled for scRNAseq analysis.