Girard Melanie, Yu Tianning, Batista Nathalia V, Yeung Karen K M, Lamorte Sara, Gao Wenting, Liu Miaoxi, McGaha Tracy L, Watts Tania H
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
J Immunol. 2025 Jul 9. doi: 10.1093/jimmun/vkaf131.
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, a sensor of cytosolic DNA, orchestrates the production of proinflammatory cytokines, chemokines, and type I interferons (IFN-Is), thereby contributing to spontaneous tumor surveillance. Intratumoral delivery of synthetic STING agonists induces IFN-I-dependent tumor regression in preclinical cancer models and is being tested clinically. In this study, we investigate the role of monocytic lineage cells (MCs) in response to STING agonist induced IFN-I signaling. We show that CCR2-deficient mice, lacking inflammatory MCs in the periphery, or Lyz2-Cre-IFNAR1fl/fl mice in which IFN-I signaling in monocytes is reduced, exhibit impaired responses to STING agonist therapy of MC38 and/or B16F10 tumors. STING agonist treatment induced CCR5-dependent migration of MCs carrying tumor antigen from the tumor to the lymph nodes. Single-cell RNA sequencing of CD45+ cells from lymph nodes and tumors of mice in which half the hematopoietic cells lack the IFNAR1 (interferon alpha/beta receptor 1) revealed that STING agonist therapy induces intrinsic IFNAR1-dependent acquisition of an inflammatory monocytic cell phenotype distinct from inflammatory classical dendritic cells (cDC) and a reduction in macrophages with a protumor TGFβ/angiogenesis transcriptome. Interleukin (IL)-18-IL-18R1 interaction was the top predicted interaction between monocytic lineage cells and CD8+ T cells or natural killer cells. Blocking IL-18 reduced IFN-γ production by CD8 T cells in lymph nodes and decreased the therapeutic efficacy of STING agonist treatment in Ccr2+/+ but not in Ccr2-/- mice. These findings support a pivotal role for IL-18 producing inflammatory monocytic lineage cells in CD8+ T cell control of melanoma following STING agonist treatment.
环磷酸鸟苷-腺苷酸合成酶-干扰素基因刺激物（cGAS-STING）通路作为胞质DNA的一种感受器，可协调促炎细胞因子、趋化因子和I型干扰素（IFN-I）的产生，从而有助于自发的肿瘤监测。在临床前癌症模型中，向肿瘤内递送合成的STING激动剂可诱导依赖IFN-I的肿瘤消退，目前正在进行临床试验。在本研究中，我们调查了单核细胞系细胞（MCs）在对STING激动剂诱导的IFN-I信号反应中的作用。我们发现，外周缺乏炎性MCs的CCR2缺陷小鼠，或单核细胞中IFN-I信号传导减少的Lyz2-Cre-IFNAR1fl/fl小鼠，对MC38和/或B16F10肿瘤的STING激动剂治疗反应受损。STING激动剂治疗诱导携带肿瘤抗原的MCs从肿瘤向淋巴结进行依赖CCR5的迁移。对造血细胞一半缺乏IFNAR1（干扰素α/β受体1）的小鼠的淋巴结和肿瘤中的CD45+细胞进行单细胞RNA测序发现，STING激动剂治疗可诱导内在的依赖IFNAR1的炎性单核细胞表型的获得，该表型不同于炎性经典树突状细胞（cDC），并且具有促肿瘤TGFβ/血管生成转录组的巨噬细胞数量减少。白细胞介素（IL）-18-IL-18R1相互作用是单核细胞系细胞与CD8+T细胞或自然杀伤细胞之间预测的最强相互作用。阻断IL-18可减少淋巴结中CD8 T细胞产生的IFN-γ，并降低Ccr2+/+小鼠而非Ccr2-/-小鼠中STING激动剂治疗的疗效。这些发现支持了在STING激动剂治疗后，产生IL-18的炎性单核细胞系细胞在CD8+T细胞控制黑色素瘤中起关键作用。
