Cao Mengdie, Peng Wang, Cheng Bin, Wang Ronghua, Chen Wei, Liu Luyao, Huang Hai, Chen Shiru, Cui Haochen, Liang JingWen, Zhou Qiaodan, Xiong Si, Bai Shuya, Liu Luoxia, Zhao Yuchong
Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Adv Sci (Weinh). 2025 May;12(20):e2413432. doi: 10.1002/advs.202413432. Epub 2025 Mar 31.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by cancer cells surrounded by affluent stromal components, which may underlie their limited response to various therapeutic interventions, including immunotherapy. Inflammatory cancer-associated fibroblasts (iCAFs), a crucial subset of CAFs within the PDAC microenvironment, play a pivotal role in shaping an immunosuppressive microenvironment. In this study, single-cell RNA sequencing analysis is performed to screen for cancer cells-secreted proteins associated with iCAF induction, and PPY (pancreatic polypeptide) is validated as a potent inducer. Unlike previously reported iCAF inducers, PPY is a gastrointestinal hormone predominantly expressed in the pancreas, suggesting that targeting it may have minimal systemic effects. Multiplex immunohistochemistry (mIHC) on human PDAC tissue microarrays, orthotopic allograft mouse models, and co-culture experiments are utilized to validate the crucial role of PPY in iCAF induction. Mechanistic studies integrating mRNA sequencing, immunoprecipitation-mass spectrometry, and molecular docking reveal that PPY induces iCAFs by activating the non-canonical NF-κB pathway through EGFR. Importantly, targeting PPY enhanced the efficacy of anti-PD-1 immunotherapy in KPC (Kras; Trp53; Pdx1-Cre) mice, as evidenced by reduced tumor burden on PET-CT imaging and improved survival. This research is expected to provide a novel strategy for improving immunotherapy in PDAC by targeting a key inducer of iCAFs.
胰腺导管腺癌（PDAC）的特征是癌细胞被丰富的基质成分所包围，这可能是其对包括免疫疗法在内的各种治疗干预反应有限的原因。炎性癌症相关成纤维细胞（iCAF）是PDAC微环境中CAF的一个关键亚群，在塑造免疫抑制微环境中起关键作用。在本研究中，进行单细胞RNA测序分析以筛选与iCAF诱导相关的癌细胞分泌蛋白，并验证胰多肽（PPY）是一种有效的诱导剂。与先前报道的iCAF诱导剂不同，PPY是一种主要在胰腺中表达的胃肠激素，这表明靶向它可能产生最小的全身影响。利用对人PDAC组织微阵列、原位同种异体移植小鼠模型和共培养实验进行的多重免疫组化（mIHC）来验证PPY在iCAF诱导中的关键作用。整合mRNA测序、免疫沉淀-质谱和分子对接的机制研究表明，PPY通过EGFR激活非经典NF-κB途径来诱导iCAF。重要的是，靶向PPY提高了抗PD-1免疫疗法在KPC（Kras；Trp53；Pdx1-Cre）小鼠中的疗效，PET-CT成像显示肿瘤负担减轻以及生存期延长证明了这一点。该研究有望通过靶向iCAF的关键诱导剂为改善PDAC的免疫疗法提供一种新策略。
