PD-L1-expressing tumor-associated macrophages are immunostimulatory and associate with good clinical outcome in human breast cancer

Tumor-associated macrophages (TAMs) are the predominant cells that express programmed cell death ligand 1 (PD-L1) within human tumors in addition to cancer cells, and PD-L1 + TAMs are generally thought to be immunosuppressive within the tumor immune microenvironment (TIME). Using single-cell transcriptomic and spatial multiplex immunofluorescence analyses, we show that PD-L1 + TAMs are mature and immunostimulatory with spatial preference to T cells. In contrast, PD-L1 – TAMs are immunosuppressive and spatially co-localize with cancer cells. Either higher density of PD-L1 + TAMs alone or ratio of PD-L1 + /PD-L1 – TAMs correlate with favorable clinical outcome in two independent cohorts of patients with breast cancer. Mechanistically, we show that PD-L1 is upregulated during the monocyte-to-macrophage maturation and differentiation process and does not require external IFN-γ stimulus. Functionally, PD-L1 + TAMs are more mature/activated and promote CD8 + T cells proliferation and cytotoxic capacity. Together, our findings reveal insights into the immunological significance of PD-L1 within the TIME. • Multi-omics study of PD-L1 expression on human TAMs • Along with functional analyses reveal PD-L1 + TAMs are mature and immunostimulatory • In contrast, PD-L1 – TAMs are immunosuppressive and pro-tumor • PD-L1 + TAMs correlate with prolonged RFS in patients with breast cancer Wang et al. examine the functional significance of PD-L1 expression on macrophages from human breast tumors. They show that PD-L1 + macrophages are immunostimulatory to T cells and associate with good clinical outcome in patients with breast cancer. In contrast, PD-L1 – macrophages are immunosuppressive and associate with poor clinical outcome.