{Reference Type}: Journal Article
{Title}: Lymph node and tumor-associated PD-L1+ macrophages antagonize dendritic cell vaccines by suppressing CD8+ T cells.
{Author}: Sprooten J;Vanmeerbeek I;Datsi A;Govaerts J;Naulaerts S;Laureano RS;Borràs DM;Calvet A;Malviya V;Kuballa M;Felsberg J;Sabel MC;Rapp M;Knobbe-Thomsen C;Liu P;Zhao L;Kepp O;Boon L;Tejpar S;Borst J;Kroemer G;Schlenner S;De Vleeschouwer S;Sorg RV;Garg AD;
{Journal}: Cell Rep Med
{Volume}: 5
{Issue}: 1
{Year}: 2024 01 16
{Factor}: 16.988
{DOI}: 10.1016/j.xcrm.2023.101377
{Abstract}: 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.