Anti-PD-1 immune checkpoint blockers can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Here, we combined intravital real-time imaging with single-cell RNA sequencing analysis and mouse models to uncover anti-PD-1 pharmacodynamics directly within tumors. We showed that effective antitumor responses required a subset of tumor-infiltrating dendritic cells (DCs), which produced interleukin 12 (IL-12). These DCs did not bind anti-PD-1 but produced IL-12 upon sensing interferon γ (IFN-γ) that was released from neighboring T cells. In turn, DC-derived IL-12 stimulated antitumor T cell immunity. These findings suggest that full-fledged activation of antitumor T cells by anti-PD-1 is not direct, but rather involves T cell:DC crosstalk and is licensed by IFN-γ and IL-12. Furthermore, we found that activating the non-canonical NF-κB transcription factor pathway amplified IL-12-producing DCs and sensitized tumors to anti-PD-1 treatment, suggesting a therapeutic strategy to improve responses to checkpoint blockade.

中文翻译：

---

成功的抗 PD-1 癌症免疫疗法需要涉及细胞因子 IFN-γ 和 IL-12 的 T 细胞-树突状细胞串扰。

抗 PD-1 免疫检查点阻滞剂可以在癌症中诱导持续的临床反应，但它们在体内的作用仍不完全清楚。在这里，我们将活体实时成像与单细胞 RNA 测序分析和小鼠模型相结合，以直接揭示肿瘤内的抗 PD-1 药效学。我们表明，有效的抗肿瘤反应需要肿瘤浸润树突状细胞 (DC) 的一个子集，它产生白细胞介素 12 (IL-12)。这些 DC 不与抗 PD-1 结合，但在感应到从相邻 T 细胞释放的干扰素 γ (IFN-γ) 时产生 IL-12。反过来，DC 衍生的 IL-12 刺激抗肿瘤 T 细胞免疫。这些发现表明，抗 PD-1 对抗肿瘤 T 细胞的全面激活不是直接的，而是涉及 T 细胞：DC 串扰，并得到 IFN-γ 和 IL-12 的许可。此外，