%0 Journal Article
%T Lymph node and tumor-associated PD-L1+ macrophages antagonize dendritic cell vaccines by suppressing CD8+ T cells.
%A Sprooten J
%A Vanmeerbeek I
%A Datsi A
%A Govaerts J
%A Naulaerts S
%A Laureano RS
%A Borràs DM
%A Calvet A
%A Malviya V
%A Kuballa M
%A Felsberg J
%A Sabel MC
%A Rapp M
%A Knobbe-Thomsen C
%A Liu P
%A Zhao L
%A Kepp O
%A Boon L
%A Tejpar S
%A Borst J
%A Kroemer G
%A Schlenner S
%A De Vleeschouwer S
%A Sorg RV
%A Garg AD
%J Cell Rep Med
%V 5
%N 1
%D 2024 01 16
%M 38232703
%F 16.988
%R 10.1016/j.xcrm.2023.101377
%X 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) responseHIGH 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.