Lymph node and tumor-associated PD-L1⁺ macrophages antagonize dendritic cell vaccines by suppressing CD8⁺ T cells

Current immunotherapies provide limited benefits against T cell-depleted tumors, calling for therapeutic innovation. Using multi-omics integration of cancer patient data, we predict a type I interferon (IFN) response^HIGH state of dendritic cell (DC) vaccines, with efficacious clinical impact. However, preclinical DC vaccines recapitulating this state by combining immunogenic cancer cell death with induction of type I IFN responses fail to regress mouse tumors lacking T cell infiltrates. Here, in lymph nodes (LNs), instead of activating CD4⁺/CD8⁺ T cells, DCs stimulate immunosuppressive programmed death-ligand 1-positive (PD-L1⁺) LN-associated macrophages (LAMs). Moreover, DC vaccines also stimulate PD-L1⁺ tumor-associated macrophages (TAMs). This creates two anatomically distinct niches of PD-L1⁺ macrophages that suppress CD8⁺ T cells. Accordingly, a combination of PD-L1 blockade with DC vaccines achieves significant tumor regression by depleting PD-L1⁺ macrophages, suppressing myeloid inflammation, and de-inhibiting effector/stem-like memory T cells. Importantly, clinical DC vaccines also potentiate T cell-suppressive PD-L1⁺ TAMs in glioblastoma patients. We propose that a multimodal immunotherapy and vaccination regimen is mandatory to overcome T cell-depleted tumors.