Transcriptional profiling of macrophages in situ in metastatic melanoma reveals localization-dependent phenotypes and function

Modulation of immune function at the tumor site could improve patient outcomes. Here, we analyze patient samples of metastatic melanoma, a tumor responsive to T cell-based therapies, and find that tumor infiltrating T cells are primarily juxtaposed to CD14(+) monocytes/macrophages rather than melanoma cells. Using immunofluorescence-guided laser capture microdissection, we analyze transcriptomes of CD3(+) T cells, CD14(+ )monocytes/macrophages, and melanoma cells in non-dissociated tissue. Stromal CD14(+) cells display a specific transcriptional signature distinct from CD14(+) cells within tumor nests. This signature contains LY75, a gene linked with antigen capture and regulation of tolerance and immunity in dendritic cells (DCs). When applied to TCGA cohorts, this gene set can distinguish patients with significantly prolonged survival in metastatic cutaneous melanoma and other cancers. Thus, the stromal CD14(+) cell signature represents a candidate biomarker and suggests that reprogramming of stromal macrophages to acquire DC function may offer a therapeutic opportunity for metastatic cancers.

Automated summary

Modulating immune function at the tumor site could improve patient outcomes. This study shows that tumor infiltrating T cells are predominantly associated with CD14(+) monocytes/macrophages rather than melanoma cells in metastatic melanoma patients. Transcriptional analysis reveals that stromal CD14(+) cells have a distinct signature compared to CD14(+) cells within tumor nests and the included LY75 gene may serve as a potential biomarker for predicting prolonged survival in metastatic cutaneous melanoma and other cancers. Reprogramming stromal macrophages to acquire dendritic cell (DC) function could offer a therapeutic opportunity for metastatic cancers.