PDF(Pubmed)
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.
摘要：
目前的免疫疗法对T细胞耗竭肿瘤的益处有限，呼吁治疗创新。使用癌症患者数据的多组学整合，我们预测I型干扰素（IFN）应答树突状细胞（DC）疫苗的高状态，具有有效的临床影响。然而,临床前DC疫苗通过将免疫原性癌细胞死亡与I型IFN反应的诱导相结合来重现这种状态，但无法逆转缺乏T细胞浸润的小鼠肿瘤。这里,在淋巴结（LN），而不是激活CD4+/CD8+T细胞，DC刺激免疫抑制性程序性死亡-配体1阳性(PD-L1+)LN相关巨噬细胞(LAMs)。此外，DC疫苗还刺激PD-L1+肿瘤相关巨噬细胞(TAMs)。这产生了抑制CD8+T细胞的PD-L1+巨噬细胞的两个解剖学上不同的生态位。因此，PD-L1阻断与DC疫苗的组合通过消耗PD-L1+巨噬细胞实现显著的肿瘤消退，抑制骨髓炎症，和去抑制效应物/干细胞样记忆T细胞。重要的是,临床DC疫苗还可增强胶质母细胞瘤患者的T细胞抑制性PD-L1+TAMs.我们建议必须采用多模式免疫疗法和疫苗接种方案来克服T细胞耗尽的肿瘤。
