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-g 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.