Department of Pathology, University of California San Francisco, San Francisco, CA, United States.
California Pacific Medical Center, Center for Melanoma Research and Treatment, Sutter Health, San Francisco, CA, United States.
Pathol Oncol Res. 2024 Sep 23;30:1611889. doi: 10.3389/pore.2024.1611889. eCollection 2024.
Advanced melanoma is considered the most aggressive and deadly form of skin cancer whose incidence has been rising over the past three decades. In the absence of treatment, the median overall survival for advanced-stage metastatic disease is less than 6 months. Although most melanomas detected at an early stage can be cured with surgery, a subset of these eventually metastasize. Therefore, a critical need exists to identify unique molecular features that would be predictive of long-term outcome and response to specific therapies. Recent promising therapeutic regimens have included the use of immune checkpoint inhibitors, such as anti-PD1 antibodies. However, the ability to identify responders and non-responders to this therapy remains elusive. To address this challenge at the molecular level, previously our laboratory identified the emergence of a stem cell phenotype associated with advanced melanoma and other aggressive forms of cancer. Underlying this phenotype is the aberrant re-expression of the embryonic morphogen "Nodal". Particularly noteworthy, we have observed Nodal to remain in advanced tumors of non-responders to standard-of-care therapies (i.e., BRAFi). This pilot study is the first proof-of-principle attempt to predict treatment response survival outcome in a small cohort of melanoma patients receiving anti-PD1 immune checkpoint inhibitor therapy - based on their Nodal expression profile. Using advanced multiplex immunohistochemistry-based digital pathology, the major finding of this preliminary study indicates that higher Nodal expression is often associated with poorer overall survival after anti-PD1 therapy, reaching nearly statistical relevance.
晚期黑色素瘤被认为是最具侵袭性和致命性的皮肤癌，其发病率在过去三十年中一直在上升。在缺乏治疗的情况下，晚期转移性疾病的中位总生存期不到 6 个月。虽然大多数在早期发现的黑色素瘤可以通过手术治愈，但其中一部分最终会转移。因此，迫切需要确定独特的分子特征，这些特征可以预测长期预后和对特定治疗的反应。最近有希望的治疗方案包括使用免疫检查点抑制剂，如抗 PD1 抗体。然而，识别对这种治疗有反应和无反应的能力仍然难以捉摸。为了解决这一分子水平上的挑战，我们实验室之前发现了一种与晚期黑色素瘤和其他侵袭性癌症相关的干细胞表型的出现。这种表型的基础是胚胎形态发生因子“Nodal”的异常重新表达。特别值得注意的是，我们观察到 Nodal 在标准治疗（即 BRAFi）的无反应者的晚期肿瘤中仍然存在。这项初步研究是第一项基于 Nodal 表达谱预测接受抗 PD1 免疫检查点抑制剂治疗的黑色素瘤患者治疗反应生存结果的原理验证尝试，这是一项基于 Nodal 表达谱预测接受抗 PD1 免疫检查点抑制剂治疗的黑色素瘤患者治疗反应生存结果的原理验证尝试。使用先进的多重免疫组织化学数字病理学，这项初步研究的主要发现表明，Nodal 表达较高通常与抗 PD1 治疗后的总体生存较差相关，几乎具有统计学意义。
