Immune-checkpoint blockers (ICB) provide limited benefit against T cell-depleted tumours, calling for therapeutic innovation. Here, we aimed at designing a new type of dendritic cell (DC) vaccine by unbiased computational integration of multi-omics data from cancer patients. In a first attempt, a DC vaccine designed to present tumor antigens from cancer cells succumbing to immunogenic cancer cell death (ICD) and to elicit high type I interferon (IFN) responses failed to induce the regression of mouse tumors lacking T cell infiltrates. In lymph nodes (LNs), instead of activating CD4⁺ and CD8⁺T cells, DCs stimulated immunosuppressive PD-L1⁺LN-associated macrophages (LAMs) via a type I IFN response. Moreover, DC vaccines of this type stimulated pre-existing, T cell-suppressive, PD-L1⁺tumour-associated macrophages (TAMs). This created a T cell-suppressive circuit of PD-L1⁺macrophages, spanning across LNs and tumours. Accordingly, DC vaccines synergised with PD-L1 blockade to deplete PD-L1⁺macrophages, suppress myeloid inflammation affecting the tumor bed and draining lymph nodes, and de-inhibit effector/stem-like memory T cells, eventually causing tumour regression. The synergistic interaction between the DC vaccine and PD-L1 blockade was lost when DCs were manipulated to lose Ifnar1or Ccr7 or when macrophages were depleted. Interestingly, clinical DC vaccines also potentiated lymphocyte-suppressive PD-L1⁺TAMs in patients bearing T cell-depleted tumours. Altogether, our results reveal the existence of a novel PD-L1⁺LAM/TAM-driven immunosuppressive pathway that can be elicited by DC vaccines, yet can be subverted for improving the outcome of immunotherapy.

中文翻译：

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淋巴结至肿瘤 PDL1+ 巨噬细胞回路拮抗树突状细胞免疫疗法

免疫检查点阻滞剂 (ICB) 对 T 细胞耗尽的肿瘤提供有限的益处，需要治疗创新。在这里，我们旨在通过对来自癌症患者的多组学数据进行无偏计算整合来设计一种新型树突状细胞 (DC) 疫苗。在第一次尝试中，设计用于呈递死于免疫原性癌细胞死亡 (ICD) 的癌细胞的肿瘤抗原并引发高 I 型干扰素 (IFN) 反应的 DC 疫苗未能诱导缺乏 T 细胞浸润的小鼠肿瘤消退。在淋巴结 (LN) 中，DC 不会激活 CD4 ⁺和 CD8 ⁺ T 细胞，而是刺激免疫抑制性 PD-L1 ⁺通过 I 型 IFN 响应的 LN 相关巨噬细胞 (LAM)。此外，这种类型的 DC 疫苗可刺激预先存在的 T 细胞抑制性 PD-L1 ⁺肿瘤相关巨噬细胞 (TAM)。^{这创建了 PD-L1 +}巨噬细胞的 T 细胞抑制回路，跨越淋巴结和肿瘤。因此，DC 疫苗与 PD-L1 阻断协同作用以耗尽 PD-L1 ⁺巨噬细胞，抑制影响肿瘤床和引流淋巴结的骨髓炎症，并去抑制效应/干细胞样记忆 T 细胞，最终导致肿瘤消退。当 DC 被操纵以丢失Ifnar1或Ccr7时，DC 疫苗和 PD-L1 阻断之间的协同相互作用丢失或者当巨噬细胞被耗尽时。有趣的是，临床 DC 疫苗还增强了患有 T 细胞耗尽肿瘤的患者的淋巴细胞抑制性 PD-L1 ^{+ TAM。总而言之，我们的结果揭示了一种新型 PD-L1 +} LAM/TAM 驱动的免疫抑制途径的存在，该途径可以由 DC 疫苗引发，但可以被破坏以改善免疫治疗的结果。