Lipidic and senescent macrophages predict progression and response to combinatorial immunotherapy in triple-negative breast cancer

Abstract

Immune cell subsets in the tumor predict prognosis. Identifying reliable subsets consistently in multiple patients is clinically important. Whats more advantageous to the field is if such subsets can be a target of immunotherapy. Here we analyzed single-cell RNA-sequencing datasets of patients with triple-negative breast cancer and identified APOE or FABP5-expressing macrophages correlated with poor prognosis. Further validation with TCGA-BRCA cohort detailed molecular signatures of these macrophages as lipidic and senescent. Our receptor-ligand mapping identified lipidic and senescent macrophages both suppress T-lymphoid and myeloid immunogenicity. Finally, we discovered that immune checkpoint therapy combined with chemotherapy reprogrammed anti-tumor microenvironment enriched with FOLR2+ macrophages facilitated T-cell activations. This suggests that lipidic and senescent macrophages could be a therapeutic target of immune checkpoint therapy.