Mallardo Domenico, Fordellone Mario, Bailey Michael, White Andrew, Simeone Ester, Festino Lucia, Vanella Vito, Trojaniello Claudia, Vitale Maria Grazia, Ottaviano Margaret, Capone Mariaelena, Costa Caterina, Ingenito Maria, Sparano Francesca, Facchini Bianca Arianna, Cavalcanti Ernesta, De Filippi Rosaria, Caracò Corrado, Cesano Alessandra, Warren Sarah, Chiodini Paolo, Budillon Alfredo, Ascierto Paolo A
Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy.
Salute Mentale e Fisica e Medicina Preventiva, University of Campania Luigi Vanvitelli, Napoli, Italy.
J Immunother Cancer. 2025 Jul 8;13(7):e011315. doi: 10.1136/jitc-2024-011315.
To identify predictive gene-expression signatures for immune-related adverse events (irAEs) in patients with melanoma treated with anti-PD-1 inhibitors, in the adjuvant therapy (AT) and first-line therapy (FLT).
This retrospective study analyzed baseline whole-blood gene expression profile from 161 patients with resected stage III or unresectable stage III-IV melanoma treated with anti-PD-1 inhibitors. RNA was extracted from baseline peripheral blood samples and profiled using the NanoString nCounter PanCancer IO 360 panel. Gene-expression signatures were identified and validated using cross-validated sparse partial least squares modeling and principal component analysis, then correlated with toxicity occurrence.
A total of 223 and 186 irAEs were observed in the AT and FLT groups, respectively, including arthralgia, colitis, and headache. Distinct gene-expression signatures significantly predicted toxicity occurrence, with variation across therapy settings. Arthralgia was predicted by immune-related and apoptotic gene signatures (eg, SMAD5, FASLG in FLT; ICOS, TGFB2 in AT), while colitis was linked to inflammatory and adhesion-related pathways. In the AT group, headache was associated with genes involved in interferon and adhesion signaling. Across both cohorts, specific signatures predicted overall irAE risk and timing. No events were observed in patients with low-risk signatures over the follow-up period. In the FLT cohort, arthralgia and cutaneous toxicities were positively associated with ORR, while arthralgia, asthenia, colitis, fatigue, and skin-related toxicities correlated with improved disease control rate. No significant association between irAEs and relapse risk was observed in the adjuvant cohort.
Whole-blood gene-expression profiling enables early identification of patients at high risk for irAEs during anti-PD-1 therapy. These predictive biomarkers may guide personalized toxicity monitoring in melanoma treatment.
识别接受抗PD-1抑制剂辅助治疗（AT）和一线治疗（FLT）的黑色素瘤患者免疫相关不良事件（irAE）的预测性基因表达特征。
这项回顾性研究分析了161例接受抗PD-1抑制剂治疗的III期切除或不可切除的III-IV期黑色素瘤患者的基线全血基因表达谱。从基线外周血样本中提取RNA，并使用NanoString nCounter泛癌IO 360面板进行分析。使用交叉验证的稀疏偏最小二乘建模和主成分分析来识别和验证基因表达特征，然后将其与毒性发生情况相关联。
在AT组和FLT组中分别观察到223例和186例irAE，包括关节痛、结肠炎和头痛。不同的基因表达特征显著预测了毒性的发生，且在不同治疗环境中存在差异。关节痛由免疫相关和凋亡基因特征预测（例如，FLT中的SMAD5、FASLG；AT中的ICOS、TGFB2），而结肠炎与炎症和粘附相关途径有关。在AT组中，头痛与参与干扰素和粘附信号传导的基因有关。在两个队列中，特定特征预测了总体irAE风险和发生时间。在随访期间，低风险特征的患者未观察到任何事件。在FLT队列中，关节痛和皮肤毒性与客观缓解率呈正相关，而关节痛、乏力、结肠炎、疲劳和皮肤相关毒性与疾病控制率的提高相关。在辅助队列中未观察到irAE与复发风险之间的显著关联。
全血基因表达谱分析能够在抗PD-1治疗期间早期识别irAE高风险患者。这些预测性生物标志物可能指导黑色素瘤治疗中的个性化毒性监测。
