Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Otolaryngology-Head and Neck Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Department of Otolaryngology-Head Neck Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Front Immunol. 2020 Dec 23;11:594775. doi: 10.3389/fimmu.2020.594775. eCollection 2020.
Interferon-stimulated gene 15 (ISG15) is known to be involved in tumor progression. We previously reported that ISG15 expressed on nasopharyngeal carcinoma (NPC) cells and related to poor prognosis of patients with NPC. We further observed that ISG15 can be secreted by NPC cell and expressed on the macrophages in situ. However, the role of ISG15 in tumor-associated macrophages (TAMs) remains poorly understood. In the present study, we found that ISG15 treatment induces macrophages with M2-like phenotype, and the enhancement of NPC cell migration and tumorigenicity. Mechanically, ISG15-induced M2-like phenotype is dependent on the interaction with its receptor, LFA-1, and engagement of SRC family kinase (SFK) signal, and the subsequent secretion of CCL18. Blocking LFA-1, or SRC signal with small molecular inhibitors, or neutralizing with anti-CCL18 antibody can impede the activation of LFA-1-SFK-CCL18 axis in ISG15-treated macrophages. Clinically, ISG15 CD163 TAMs related to impaired survival of patients and advanced tumor stage of NPC. Furthermore, we found ISG15 CD163 macrophages inhibited antitumor CD8 cells responses in NPC. Together, our findings suggested tumor cell-secreted ISG15, which acted as a tumor microenvironmental factor, induces M2-like phenotype, promoting tumor progression and suppression of cytotoxic T lymphocyte response.
干扰素刺激基因 15（ISG15）已知参与肿瘤进展。我们之前报道过，ISG15 在鼻咽癌（NPC）细胞中表达，与 NPC 患者的预后不良有关。我们进一步观察到，ISG15 可以由 NPC 细胞分泌，并在原位巨噬细胞上表达。然而，ISG15 在肿瘤相关巨噬细胞（TAMs）中的作用仍知之甚少。在本研究中，我们发现 ISG15 处理诱导巨噬细胞呈现 M2 样表型，并增强 NPC 细胞的迁移和致瘤性。从机制上讲，ISG15 诱导的 M2 样表型依赖于其受体 LFA-1 的相互作用和 SRC 家族激酶（SFK）信号的参与，以及随后 CCL18 的分泌。用小分子抑制剂阻断 LFA-1 或 SRC 信号，或用抗 CCL18 抗体中和，可阻碍 ISG15 处理的巨噬细胞中 LFA-1-SFK-CCL18 轴的激活。临床上，与 NPC 患者生存受损和肿瘤晚期相关的 ISG15 CD163 TAMs。此外，我们发现 ISG15 CD163 巨噬细胞抑制 NPC 中的抗肿瘤 CD8 细胞反应。总之，我们的研究结果表明，肿瘤细胞分泌的 ISG15 作为肿瘤微环境因子，诱导 M2 样表型，促进肿瘤进展并抑制细胞毒性 T 淋巴细胞反应。
