Department of Immunology, University of Pittsburgh, 5051 Centre Avenue, Pittsburgh, PA 15213, USA; UPMC Hillman Cancer Center, 5115 Centre Avenue, Pittsburgh, PA 15232, USA.
Wake Forest University, Department of Radiation Oncology, 1 Medical Center Blvd., Winston-Salem, NC 27157, USA.
Mol Immunol. 2024 Jun;170:156-169. doi: 10.1016/j.molimm.2024.04.012. Epub 2024 Apr 30.
Type-I and -III interferons play a central role in immune rejection of pathogens and tumors, thus promoting immunogenicity and suppressing tumor recurrence. Double strand RNA is an important ligand that stimulates tumor immunity via interferon responses. Differentiation of embryonic stem cells to pluripotent epithelial cells activates the interferon response during development, raising the question of whether epithelial vs. mesenchymal gene signatures in cancer potentially regulate the interferon pathway as well. Here, using genomics and signaling approaches, we show that Grainyhead-like-2 (GRHL2), a master programmer of epithelial cell identity, promotes type-I and -III interferon responses to double-strand RNA. GRHL2 enhanced the activation of IRF3 and relA/NF-kB and the expression of IRF1; a functional GRHL2 binding site in the IFNL1 promoter was also identified. Moreover, time to recurrence in breast cancer correlated positively with GRHL2 protein expression, indicating that GRHL2 is a tumor recurrence suppressor, consistent with its enhancement of interferon responses. These observations demonstrate that epithelial cell identity supports interferon responses in the context of cancer.
I 型和 III 型干扰素在免疫排斥病原体和肿瘤方面发挥着核心作用，从而促进了免疫原性并抑制了肿瘤复发。双链 RNA 是一种重要的配体，可通过干扰素反应刺激肿瘤免疫。胚胎干细胞向多能上皮细胞的分化在发育过程中激活了干扰素反应，这就提出了一个问题，即在癌症中上皮与间充质基因特征是否可能同样调节干扰素途径。在这里，我们使用基因组学和信号转导方法表明，颗粒蛋白样 2（GRHL2）是上皮细胞特征的主要编程器，可促进双链 RNA 的 I 型和 III 型干扰素反应。GRHL2 增强了 IRF3 和 relA/NF-kB 的激活以及 IRF1 的表达；还确定了 IFNL1 启动子中的功能性 GRHL2 结合位点。此外，乳腺癌的复发时间与 GRHL2 蛋白表达呈正相关，这表明 GRHL2 是肿瘤复发的抑制因子，与其增强干扰素反应的作用一致。这些观察结果表明，上皮细胞特征在癌症背景下支持干扰素反应。
