FOLR2⁺ Macrophages Are Associated with T-cell Infiltration and Improved Prognosis

Tumor-associated macrophages (TAM) are present within the tumor microenvironment of breast cancer, and their presence has been correlated with poor prognosis. These cells are typically considered immunosuppressive and protumorigenic; however, some studies have demonstrated a protective role for these cells, suggesting the presence of a heteroge­neous TAM population within the tumor that could impact the development of TAM-targeting antitumor therapies. Therefore, Nalio Ramos, Missolo-Koussou, and colleagues used single-cell RNA sequencing of CD14⁺/HLA-DR⁺/APOE⁺ cells from both primary breast tumors and corresponding metastatic lymph nodes to assess the heterogeneity of this cellular compartment. Two subsets of macrophages were found, with one defined by FOLR2 and the other by TREM2/CADM1. Further investigation into the FOLR2⁺ macrophages revealed their presence in normal healthy breast tissue, with their frequency but not absolute number decreasing in tumors, indicating that they are tissue-resident macrophages. These FOLR2⁺ macrophages were found to be associated with breast cancer survival, with their high density being correlated with better overall survival. Additionally, this macrophage subset is present across many diverse cancer types, and spatial distribution revealed their presence mainly within the tumor stroma, while TREM2⁺ macrophages tend to localize close to the tumor nest. Correlation of the FOLR2 gene signature with other antitumor immune cells, such as CD8⁺ T cells and dendritic cells, was observed, as was the enrichment of pathways including antigen processing and T-cell receptor/PD-1 signaling with CD8⁺ T cells also being found to interact with FOLR2⁺ macrophages, likely resulting in activation of these T cells. Moreover, these FOLR2⁺ macrophages were found to be evolutionarily conserved between mice and humans, with the transcriptomic profiles of murine Folr2⁺ macrophages demonstrating alterations dependent on tumor size, which allowed for the activation and priming of CD8⁺ T cells. Thus, this work demonstrates the heterogeneity of macrophage populations within the tumor and suggests tissue-resident FOLR2⁺ macrophages can promote lymphocyte infiltration and improve patient outcome.

Nalio Ramos R, Missolo-Koussou Y, Gerber-Ferder Y, Bromley CP, Bugatti M, Núñez NG, et al. Tissue-resident FOLR2⁺ macrophages associate with CD8⁺ T cell infiltration in human breast cancer. Cell 2022;185:1189–207.e25.

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