PD-L1 and Notch as novel biomarkers in pancreatic sarcomatoid carcinoma: a pilot study

The improved immunological understanding revealed the tumor microenvironment as an appealing driver to restore the immune response against cancer cells resulting in a paradigm shift in the oncology field. However, the complexity of the tumor milieu suggests the role of several pathways linking in immunomodulation mechanisms. Pancreatic cancer represents a model of the intricate relationship between malignant cells and their surrounding neighborhood. In this study, we analyzed, retrospectively, six cases of rare pancreatic sarcomatoid carcinoma (PSC) and evaluated the expression of PD-L1 and Notch, aiming to explore new attributes in immunophenotype. PD-L1 CPS ≥ 1was common in PSCs (83%) with half samples expressing PD-L1 CPS ≥ 50. Notch1 and Notch3 demonstrated a high range of expression. A direct significant correlation between PD-L1 and Notch3 overexpression (r = 0.7; p = 0.036) has been observed. Immunofluorescence studies revealed a co-localization of Notch3 and PD-L1 when both proteins were over-expressed within cytoplasmic or membranous compartments of the same cells. Our data identify a unique biological characterization of this rare pancreatic histotype. These findings provide a rationale for future studies evaluating the potential crosstalk between PD-L1/PD-1 axis and Notch pathways and prompting the development of novel therapeutics strategy.

随着免疫学认知的不断深化，肿瘤微环境被证实是重塑抗肿瘤免疫应答的关键驱动因素之一，这一发现推动了肿瘤学领域的研究范式革新。然而，肿瘤微环境的复杂性意味着多种通路共同参与免疫调控机制。胰腺癌是研究恶性肿瘤细胞与其周围微环境间复杂相互作用的经典模型。本研究回顾性分析了6例罕见的胰腺肉瘤样癌（pancreatic sarcomatoid carcinoma, PSC）病例，并检测了PD-L1与Notch的表达情况，以期挖掘免疫表型的全新特征。PD-L1联合阳性评分（Combined Positive Score, CPS）≥1的病例在PSC中占比达83%，其中半数样本的CPS≥50。Notch1与Notch3均呈现较高水平的表达。研究观察到PD-L1过表达与Notch3过表达之间存在显著直接相关性（r=0.7，P=0.036）。免疫荧光实验证实，当两种蛋白在同一细胞的胞质或膜结构中过表达时，Notch3与PD-L1存在共定位现象。本研究的数据明确了这一罕见胰腺组织学亚型的独特生物学特征。本研究结果为后续探索PD-L1/PD-1轴与Notch通路间潜在的交互调控机制提供了理论依据，同时也为新型治疗策略的开发指明了方向。