Abstract
Metastasis of melanoma significantly worsens prognosis; thus, therapeutic interventions that prevent metastasis could improve patient outcomes. Here, we show using humanized mice that colonization of distant visceral organs with melanoma is dependent upon a human CD33+CD11b+CD117+ progenitor cell subset comprising <4% of the human CD45+ leukocytes. Metastatic tumor-infiltrating CD33+ cells from patients and humanized (h)NSG-SGM3 mice showed converging transcriptional profiles. Single-cell RNA-seq analysis identified a gene signature of a KIT/CD117-expressing CD33+ subset that correlated with decreased overall survival in a TCGA melanoma cohort. Thus, human CD33+CD11b+CD117+ myeloid cells represent a novel candidate biomarker as well as a therapeutic target for metastatic melanoma.
Highlights
Mechanisms sustaining the growth of human melanoma in distant organs remain poorly defined
Improved survival has been documented for patients with metastatic melanoma treated with B-raf proto-oncogene serine/threonine kinase– and/ or mitogen-activated protein kinase kinase–targeted therapies (Flaherty et al, 2016; Long et al, 2017) or with blocking antibodies targeting CTL-associated protein (CTLA)-4 (Hodi et al, 2010) and/ or programmed death (PD)-1 (Wolchok et al, 2017)
Metastatic melanoma tumors in patients and in humanized mice are infiltrated with CD33+ myeloid cells To define the landscape of leukocytes in metastatic melanoma, we analyzed transcriptional profiles of metastatic melanoma
Summary
Mechanisms sustaining the growth of human melanoma in distant organs remain poorly defined. Distant organ colonization is dependent upon hCD33+ myeloid cells Tissue examination revealed close proximity of hCD33+ cells and melanoma cells in the liver and spleen of hNSG-SGM3 mice (Fig. 3 A).
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