巨噬细胞 STING 信号通路通过 4-1BBL/4-1BB 共刺激促进 NK 细胞抑制结直肠癌肝转移。
Macrophage STING signaling promotes NK cell to suppress colorectal cancer liver metastasis via 4-1BBL/4-1BB co-stimulation.
机构信息
Hepatobiliary Center, Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China.
Department of Head and Neck Surgical Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
出版信息
J Immunother Cancer. 2023 Mar;11(3). doi: 10.1136/jitc-2022-006481.
BACKGROUND AND AIMS
Macrophage innate immune response plays an important role in tumorigenesis. However, the role and mechanism of macrophage STING signaling in modulating tumor microenvironment to suppress tumor growth at secondary sites remains largely unclear.
METHODS
STING expression was assessed in liver samples from patients with colorectal cancer (CRC) liver metastasis. Global or myeloid stimulator of interferon gene (STING)-deficient mice, myeloid NOD-like receptor protein 3 (NLRP3)-deficient mice, and wild-type (WT) mice were subjected to a mouse model of CRC liver metastasis by intrasplenic injection of murine colon carcinoma cells (MC38). Liver non-parenchymal cells including macrophages and natural killer (NK) cells were isolated for flow cytometry analysis. Bone marrow-derived macrophages pretreated with MC38 were co-cultured with splenic NK cells for in vitro studies.
RESULTS
Significant activation of STING signaling were detected in adjacent and tumor tissues and intrahepatic macrophages. Global or myeloid STING-deficient mice had exacerbated CRC liver metastasis and shorten survival, with decreased intrahepatic infiltration and impaired antitumor function of NK cells. Depletion of NK cells in WT animals increased their metastatic burden, while no significant effects were observed in myeloid STING-deficient mice. STING activation contributed to the secretion of interleukin (IL)-18 and IL-1β by macrophages, which optimized antitumor activity of NK cells by promoting the expression of 4-1BBL in macrophages and 4-1BB in NK cells, respectively. Moreover, MC38 treatment activated macrophage NLRP3 signaling, which was inhibited by STING depletion. Myeloid NLRP3 deficiency increased tumor burden and suppressed activation of NK cells. NLRP3 activation by its agonist effectively suppressed CRC liver metastasis in myeloid SITNG-deficient mice.
CONCLUSIONS
We demonstrated that STING signaling promoted NLRP3-mediated IL-18 and IL-1β production of macrophages to optimize the antitumor function of NK cells via the co-stimulation signaling of 4-1BBL/4-1BB.
背景与目的
巨噬细胞固有免疫反应在肿瘤发生中起着重要作用。然而，巨噬细胞 STING 信号在调节肿瘤微环境以抑制次级部位肿瘤生长中的作用和机制在很大程度上仍不清楚。
方法
评估了结直肠癌（CRC）肝转移患者肝组织中 STING 的表达。通过向小鼠脾脏内注射小鼠结肠癌细胞（MC38），使 STING 全身性或髓样缺陷型小鼠、髓样 NOD 样受体蛋白 3（NLRP3）缺陷型小鼠和野生型（WT）小鼠发生 CRC 肝转移模型。分离肝非实质细胞，包括巨噬细胞和自然杀伤（NK）细胞，进行流式细胞术分析。用 MC38 预处理的骨髓来源的巨噬细胞与脾 NK 细胞共培养进行体外研究。
结果
在相邻组织和肿瘤组织以及肝内巨噬细胞中检测到 STING 信号的显著激活。全身性或髓样 STING 缺陷型小鼠的 CRC 肝转移加剧，生存时间缩短，肝内浸润减少，NK 细胞抗肿瘤功能受损。在 WT 动物中耗尽 NK 细胞增加了它们的转移负担，但在髓样 STING 缺陷型小鼠中没有观察到明显的影响。STING 激活导致巨噬细胞分泌白细胞介素（IL）-18 和 IL-1β，通过分别促进巨噬细胞中 4-1BBL 和 NK 细胞中 4-1BB 的表达，优化 NK 细胞的抗肿瘤活性。此外，MC38 处理激活了巨噬细胞 NLRP3 信号，而 STING 耗竭抑制了该信号。髓样 NLRP3 缺陷增加了肿瘤负担并抑制了 NK 细胞的激活。NLRP3 激动剂的激活可有效抑制髓样 STING 缺陷型小鼠的 CRC 肝转移。
结论
我们证明 STING 信号通过 4-1BBL/4-1BB 的共刺激信号促进巨噬细胞 NLRP3 介导的 IL-18 和 IL-1β 的产生，从而优化 NK 细胞的抗肿瘤功能。
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