| First Author | Sprooten J | Year | 2024 |
| Journal | Cell Rep Med | Volume | 5 |
| Issue | 1 | Pages | 101377 |
| PubMed ID | 38232703 | Mgi Jnum | J:350721 |
| Mgi Id | MGI:7664304 | Doi | 10.1016/j.xcrm.2023.101377 |
| Citation | Sprooten J, et al. (2024) Lymph node and tumor-associated PD-L1(+) macrophages antagonize dendritic cell vaccines by suppressing CD8(+) T cells. Cell Rep Med 5(1):101377 |
| abstractText | 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. |
