Joaquin Garcia Andrea, Semba Takashi, Rediti Mattia, McGrail Daniel J, Xie Xuemei, Wang Xiaoping, Rampa Dileep R, Venet David, Buisseret Laurence, Majjaj Samira, Kammler Roswitha, Colleoni Marco, Loi Sherene, Viale Giuseppe, Regan Meredith M, Rothé Françoise, Sotiriou Christos, Ueno Naoto T
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
iScience. 2025 Jun 20;28(8):112964. doi: 10.1016/j.isci.2025.112964. eCollection 2025 Aug 15.
Phosphorylation of the JNK (pJNK) protein promotes an immunosuppressive tumor microenvironment (TME), enhancing aggressiveness in inflammatory triple-negative breast cancer (TNBC). This study evaluated the role of JNK signaling using a gene signature. RNA sequencing was performed on 347 TNBC tumors from the phase 3 International Breast Cancer Study Group (IBCSG) 22-00 trial, which evaluated adjuvant low-dose cyclophosphamide and methotrexate (CM). Immune-related tumors were identified by TNBC subtype or tumor-infiltrating lymphocytes (TILs). Associations between JNK and outcomes were analyzed using Cox models. Low pJNK levels were associated with better disease-free survival (DFS) in immune-related tumors. These tumors also had lower Treg levels and higher CD8/Treg ratios. Notably, immunomodulatory (IM) tumors with high pJNK showed improved DFS when treated with CM. High pJNK expression identifies immunosuppressive TMEs with poor prognosis in inflamed TNBC. However, these tumors may benefit from CM, supporting pJNK as a potential biomarker for immunotherapy strategies.
JNK（磷酸化JNK，pJNK）蛋白的磷酸化促进免疫抑制性肿瘤微环境（TME），增强炎性三阴性乳腺癌（TNBC）的侵袭性。本研究使用基因特征评估了JNK信号传导的作用。对来自3期国际乳腺癌研究组（IBCSG）22 - 00试验的347例TNBC肿瘤进行了RNA测序，该试验评估了辅助低剂量环磷酰胺和甲氨蝶呤（CM）。通过TNBC亚型或肿瘤浸润淋巴细胞（TILs）鉴定免疫相关肿瘤。使用Cox模型分析JNK与预后之间的关联。在免疫相关肿瘤中，低pJNK水平与更好的无病生存期（DFS）相关。这些肿瘤的调节性T细胞（Treg）水平也较低，CD8/Treg比值较高。值得注意的是，高pJNK的免疫调节（IM）肿瘤在接受CM治疗时DFS有所改善。高pJNK表达可识别炎症性TNBC中预后不良的免疫抑制性TME。然而，这些肿瘤可能从CM中获益，支持pJNK作为免疫治疗策略的潜在生物标志物。
