Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.
Division of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
Nat Cancer. 2023 Sep;4(9):1292-1308. doi: 10.1038/s43018-023-00610-2. Epub 2023 Jul 31.
Recent studies suggest that BRAF-mutated melanomas in particular respond to dual anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibition (ICI). Here we identified an over-representation of interleukin (IL)-17-type 17 helper T (T17) gene expression signatures (GES) in BRAF-mutated tumors. Moreover, high baseline IL-17 GES consistently predicted clinical responses in dual-ICI-treated patient cohorts but not in mono anti-CTLA-4 or anti-PD-1 ICI cohorts. High IL-17 GES corresponded to tumor infiltration with T cells and neutrophils. Accordingly, high neutrophil infiltration correlated with clinical response specifically to dual ICI, and tumor-associated neutrophils also showed strong IL-17-T17 pathway activity and T cell activation capacity. Both the blockade of IL-17A and the depletion of neutrophils impaired dual-ICI response and decreased T cell activation. Finally, high IL-17A levels in the blood of patients with melanoma indicated a higher global T17 cytokine profile preceding clinical response to dual ICI but not to anti-PD-1 monotherapy, suggesting a future role as a biomarker for patient stratification.
最近的研究表明，特别是 BRAF 突变型黑色素瘤对双抗程序性细胞死亡蛋白 1（PD-1）和抗细胞毒性 T 淋巴细胞相关蛋白 4（CTLA-4）免疫检查点抑制剂（ICI）的反应。在这里，我们发现 BRAF 突变型肿瘤中白细胞介素（IL）-17 型 17 辅助 T（T17）基因表达特征（GES）过度表达。此外，高基线 IL-17 GES 一致预测双 ICI 治疗患者队列的临床反应，但不能预测单抗 CTLA-4 或抗 PD-1 ICI 队列的临床反应。高 IL-17 GES 与 T 细胞和中性粒细胞浸润肿瘤相关。相应地，高中性粒细胞浸润与双 ICI 的临床反应特异性相关，肿瘤相关的中性粒细胞也表现出强烈的 IL-17-T17 通路活性和 T 细胞激活能力。IL-17A 的阻断和中性粒细胞的耗竭均损害了双 ICI 反应并降低了 T 细胞的激活。最后，黑色素瘤患者血液中高 IL-17A 水平表明在双 ICI 治疗前存在更高的全局 T17 细胞因子谱，但在抗 PD-1 单药治疗前不存在，这表明其可能成为患者分层的生物标志物。
