Department of Oral Pathology, Howard University, 600 W Street NW, Washington, DC, 20059, USA.
Cancer Center, Howard University, 2041 Georgia Avenue NW, Washington, DC, 20059, USA.
Sci Rep. 2023 Oct 28;13(1):18476. doi: 10.1038/s41598-023-45797-7.
The innate immune stimulator of interferon genes (STING) pathway is known to activate type I interferons (IFN-I) and participate in generating antitumor immunity. We previously produced hDT806, a recombinant diphtheria immunotoxin, and demonstrated its efficacy against head and neck squamous cell carcinoma (HNSCC). However, it's unknown whether the tumor-intrinsic STING plays a role in the anti-HNSCC effects of hDT806. In this study, we investigated the innate immune modulation of hDT806 on HNSCC. hDT806 significantly upregulated the level of STING and the ratio of p-TBK1/TBK1 in the HNSCC cells. Moreover, intratumoral hDT806 treatment increased the expression of STING-IFN-I signaling proteins including IFNA1, IFNB, CXCL10 and MX1, a marker of IFN-I receptor activity, in the HNSCC xenografts. Overexpression of STING mimicked the hDT806-induced upregulation of the STING-IFN-I signaling and induced apoptosis in the HNSCC cells. In the mouse xenograft models of HNSCC with STING overexpression, we observed a significant suppression of tumor growth and reduced tumor weight with increased apoptosis compared to their control xenograft counterparts without STING overexpression. Collectively, our data revealed that hDT806 may act as a stimulator of tumor-intrinsic STING-IFN-I signaling to inhibit tumor growth in HNSCC.
干扰素基因（STING）途径的先天免疫刺激物已知可激活 I 型干扰素（IFN-I）并参与产生抗肿瘤免疫。我们之前生产了 hDT806，一种重组白喉免疫毒素，并证明了其对头颈鳞状细胞癌（HNSCC）的疗效。然而，hDT806 是否通过肿瘤内在的 STING 发挥作用来抑制 HNSCC 尚不清楚。在这项研究中，我们研究了 hDT806 对 HNSCC 的先天免疫调节作用。hDT806 可显著上调 HNSCC 细胞中的 STING 水平和 p-TBK1/TBK1 比值。此外，肿瘤内 hDT806 治疗可增加 HNSCC 异种移植物中 STING-IFN-I 信号蛋白的表达，包括 IFNA1、IFNB、CXCL10 和 MX1，这是 IFN-I 受体活性的标志物。STING 的过表达模拟了 hDT806 诱导的 STING-IFN-I 信号的上调，并诱导了 HNSCC 细胞的凋亡。在 STING 过表达的 HNSCC 小鼠异种移植模型中，与未过表达 STING 的对照组相比，我们观察到肿瘤生长受到显著抑制，肿瘤重量减轻，凋亡增加。总之，我们的数据表明，hDT806 可能作为肿瘤内在的 STING-IFN-I 信号的刺激物，抑制 HNSCC 中的肿瘤生长。
