Current immunotherapeutic approaches are tailored towards biomarkers and mechanisms presented in the primary tumor microenvironment, yet few are designed against targets that arise in the metastatic site. In a recent Cancer Discovery article, Yofe and colleagues spatially and temporally mapped the evolving breast tumor metastatic environment within the lung at single-cell resolution to identify immunologic cell types and mechanisms underlying the formation of metastatic nodules. The authors identified myeloid cell, monocyte, and neutrophil phenotypes as the most significant differences between the primary tumor and metastatic site. The authors also revealed the existence of a metastasis-specific population of macrophages expressing Trem2 in both human and murine models that exhibit immunosuppressive features. Interestingly, Trem2+ macrophages are enriched at the invasive border of metastatic nodules compared with the metastatic core, suggesting they play an exclusionary role within the site. Characterization of the premetastatic lung in conjunction with pseudotime lineage analysis revealed that Fn1+ monocytes precede metastasis formation and are the likely source of Trem2+ macrophages in developed nodules. This study supports the characterization of metastatic immune microenvironments to identify novel immunotherapeutic targets that may not exist within the primary site but play a significant role in patient outcome.
©2023 American Association for Cancer Research.