CCL-20与CXCL-8基因过表达促进肿瘤逃逸与对程序性细胞死亡蛋白-1 (PD-1) 抑制剂 cemiplimab 的耐药性，在局部晚期及转移性皮肤鳞状细胞癌患者中的作用

Overexpression of CCL-20 and CXCL-8 genes enhances tumor escape and resistance to cemiplimab, a programmed cell death protein-1 (PD-1) inhibitor, in patients with locally advanced and metastatic cutaneous squamous cell carcinoma

OncoImmunology

影响因子:6.3

分区:医学2区 / 免疫学2区肿瘤学2区

发表日期:2024

作者: Vincenzo De Falco, Stefania Napolitano, Renato Franco, Federica Zito Marino, Luigi Formisano, Daniela Esposito, Gabriella Suarato, Rossella Napolitano, Alfonso Esposito, Francesco Caraglia, Maria Cristina Giugliano, Eleonora Cioli, Vincenzo Famiglietti, Roberto Bianco, Giuseppe Argenziano, Andrea Ronchi, Davide Ciardiello, Valerio Nardone, Emma D'Ippolito, Sara Del Tufo, Fortunato Ciardiello, Teresa Troiani

DOI: 10.1080/2162402X.2024.2388315

摘要

Cemiplimab在皮肤鳞状细胞癌（cSCC）中展现出相关的临床活性，但原发性及获得性免疫治疗耐药机制仍不清楚。我们收集了在意大利两所大学中心接受cemiplimab治疗的局部晚期和/或转移性cSCC患者的临床数据。此外，采用Nanostring技术平台对20个肿瘤组织样本（9例对cemiplimab反应者和11例非反应者）中770个与癌症及免疫相关的基因进行了表达分析。共纳入81名患者，中位年龄82岁。经过中位随访16.4个月后，12和24个月的无进展生存期（PFS）分别为53%和42%；而12和24个月的总生存率（OS）分别为71%和61%。治疗耐受良好。总反应率（ORR）为58%，疾病控制率（DCR）为77.8%。反应者与非反应者样本中的基因表达差异显著，尤其是涉及免疫调节的基因。cemiplimab耐药肿瘤与CCL-20和CXCL-8的过表达相关。cemiplimab在实际临床cSCC患者中的疗效和安全性得到确认。CCL-20和CXCL-8的过表达可能是免疫治疗无反应的生物标志物。

Abstract

Cemiplimab has demonstrated relevant clinical activity in cutaneous squamous cell carcinoma (cSCC) but mechanisms of primary and acquired resistance to immunotherapy are still unknown. We collected clinical data from locally advanced and/or metastatic cSSC patients treated with cemiplimab in two Italian University centers. In addition, gene expression analysis by using Nanostring Technologies platform to evaluate 770 cancer- and immune-related genes on 20 tumor tissue samples (9 responders and 11 non-responders to cemiplimab) was performed. We enrolled 81 patients with a median age of 82 years. After 16.4 months of median follow-up, 12- and 24-months PFS were 53% and 42%, respectively; while 12- and 24-months OS were 71% and 61%, respectively. Treatment was well tolerated. Overall response rate (ORR) was 58%, with a disease control rate (DCR) of 77.8%. The difference between genes expressed in responder versus non-responder patient samples was substantial, particularly for genes involved in immune system regulation. Cemiplimab-resistant tumors were associated with over-expression of CCL-20 and CXCL-8. Cemiplimab confirmed efficacy and safety data in real-life cSCC patients. Overexpression of CCL-20 and CXCL-8 could represent biomarkers of lack of response to immunotherapy.