Esposito Daniela, Napolitano Fabiana, Maresca Daniela Claudia, Scala Marcella, Amato Annarita, Belli Stefania, Ascione Claudia Maria, Vallefuoco Angela, Attanasio Giovanna, Somma Fabio, Ianaro Angela, Russo Daniela, Varricchio Silvia, Mascolo Massimo, Costa Claudia, Villani Alessia, Scalvenzi Massimiliano, Orlandino Gianfranco, Troiani Teresa, Servetto Alberto, Bianco Roberto, Ercolano Giuseppe, Formisano Luigi
Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
Department of Pharmacy, University of Naples Federico II, Naples, Italy.
J Immunother Cancer. 2025 Jan 11;13(1):e010421. doi: 10.1136/jitc-2024-010421.
Anti-programmed cell death 1 (PD1) is the first-choice treatment in patients with advanced cutaneous squamous cell carcinoma (cSCC), when curative options are unavailable. However, reliable biomarkers for patient selection are still lacking.
In this translational study, clinical annotations, tissue and liquid biopsies were acquired to investigate the association between sustained objective responses and transcriptional profiles, immune cell dynamics in tumor tissue and peripheral blood samples, as well as circulating cytokine levels.
First, we investigated the baseline characteristics of the immune landscape of cSCC biopsies. Gene Set Enrichment Analysis showed upregulation of interleukin (IL)2/STAT5 pathways and downregulation of Interferon signatures in non-responder patients compared with responders. Next, we studied the early changes induced by cemiplimab in tissue biopsies. Notably, after only three weeks, cemiplimab treatment induced an increase in B cells and CD8+ T cells in responders, whereas their abundance decreased in non-responder patients. Moreover, analyzing differentially expressed genes modulated early during treatment, compared with baseline biopsies, we found that IL1β and IL8 exhibited early downregulation in responder patients' tumor specimens. We assessed whether changes in the local tumor microenvironment were mirrored in peripheral blood. Similar to tissue findings, no changes were observed in the whole T regulatory (Treg) population, although PD1+ Tregs, which were downregulated in responder patients (vs T0), showed a rebound enrichment in non-responders after three cycles of cemiplimab. Finally, IL8 mirrored the tissue results, unlike IL1β, with early (T1) and then sustained (T3) downregulation of its levels in responder patients, while increased in non-responders.
Taken together, these findings shed light on the significance of early transcriptomic and immune cell modulation in predicting responses to cemiplimab therapy. Additionally, our data suggest that IL8 levels in peripheral blood offer promising avenues for personalized treatment selection and response assessment in patients with cSCC receiving cemiplimab, while PD1+Tregs can be followed longitudinally to monitor response to therapy.
对于无法进行治愈性治疗的晚期皮肤鳞状细胞癌（cSCC）患者，抗程序性细胞死亡1（PD1）是首选治疗方法。然而，仍缺乏用于患者选择的可靠生物标志物。
在这项转化研究中，获取了临床注释、组织和液体活检样本，以研究持续客观反应与转录谱、肿瘤组织和外周血样本中的免疫细胞动态以及循环细胞因子水平之间的关联。
首先，我们研究了cSCC活检样本免疫格局的基线特征。基因集富集分析显示，与有反应的患者相比，无反应患者中白细胞介素（IL）2/信号转导和转录激活因子5（STAT5）通路上调，干扰素特征下调。接下来，我们研究了西米普利单抗在组织活检中诱导的早期变化。值得注意的是，仅三周后，西米普利单抗治疗就使有反应的患者体内B细胞和CD8 + T细胞增加，而在无反应的患者中其数量减少。此外，与基线活检样本相比，分析治疗早期调节的差异表达基因，我们发现IL1β和IL8在有反应患者的肿瘤标本中早期下调。我们评估了外周血中是否反映了局部肿瘤微环境的变化。与组织结果相似，尽管在有反应的患者中（与T0相比）PD1 +调节性T细胞（Treg）下调，但在西米普利单抗三个周期后，无反应患者中显示出反弹富集，整个Treg群体未观察到变化。最后，与IL1β不同，IL8反映了组织结果，有反应患者中其水平早期（T1）然后持续（T3）下调，而在无反应患者中升高。
综上所述，这些发现揭示了早期转录组学和免疫细胞调节在预测西米普利单抗治疗反应中的重要性。此外，我们的数据表明，外周血中的IL8水平为接受西米普利单抗治疗的cSCC患者的个性化治疗选择和反应评估提供了有前景的途径，而PD1 + Tregs可以纵向跟踪以监测治疗反应。
