靶向Pin1与免疫化疗相结合可治疗胰腺癌，这一成果由美国哈佛医学院贝斯以色列女执事医疗中心Kun Ping Lu和Xiao Zhen Zhou小组合作经过不懈努力而取得。相关论文在线发表在2021年8月12日出版的《细胞》杂志上。
在本研究中，研究人员发现Pin1在癌细胞和癌症相关成纤维细胞(CAF)中都过度表达，并且与胰腺导管腺癌(PDAC)患者的低存活率相关。在不同模型系统中，临床上可用的靶向Pin1药物与抗PD-1和吉西他滨相联合可使诱导侵袭性PDAC完全消除或持续缓解。从机制上讲，Pin1通过作用于CAF来诱导促纤维化和免疫抑制性肿瘤微环境 (TME)，并诱导癌细胞中PD-1配体PD-L1和吉西他滨转运蛋白ENT1的溶酶体降解，此外还激活多种癌症通路。因此，抑制Pin1可同时阻断多种癌症通路，破坏促纤维化和免疫抑制性TME，并上调PD-L1和 ENT1，从而使PDAC可通过免疫化学疗法治愈。
据了解，PDAC对当前疗法具有强烈抵抗性的原因在于其固有的肿瘤异质性和高度紧促的结缔组织和免疫抑制性TME。特异性脯氨酸异构酶Pin1调节多种癌症途径，但其在TME和癌症免疫治疗中的作用尚不清楚。
附：英文原文
Title: Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy
Author: Kazuhiro Koikawa, Shin Kibe, Futoshi Suizu, Nobufumi Sekino, Nami Kim, Theresa D. Manz, Benika J. Pinch, Dipikaa Akshinthala, Ana Verma, Giorgio Gaglia, Yutaka Nezu, Shizhong Ke, Chenxi Qiu, Kenoki Ohuchida, Yoshinao Oda, Tae Ho Lee, Babara Wegiel, John G. Clohessy, Nir London, Sandro Santagata, Gerburg M. Wulf, Manuel Hidalgo, Senthil K. Muthuswamy, Masafumi Nakamura, Nathanael S. Gray, Xiao Zhen Zhou, Kun Ping Lu
Issue&Volume: 2021-08-12
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is characterized by notorious resistance tocurrent therapies attributed to inherent tumor heterogeneity and highly desmoplasticand immunosuppressive tumor microenvironment (TME). Unique proline isomerase Pin1regulates multiple cancer pathways, but its role in the TME and cancer immunotherapyis unknown. Here, we find that Pin1 is overexpressed both in cancer cells and cancer-associatedfibroblasts (CAFs) and correlates with poor survival in PDAC patients. Targeting Pin1using clinically available drugs induces complete elimination or sustained remissionsof aggressive PDAC by synergizing with anti-PD-1 and gemcitabine in diverse modelsystems. Mechanistically, Pin1 drives the desmoplastic and immunosuppressive TME byacting on CAFs and induces lysosomal degradation of the PD-1 ligand PD-L1 and thegemcitabine transporter ENT1 in cancer cells, besides activating multiple cancer pathways.Thus, Pin1 inhibition simultaneously blocks multiple cancer pathways, disrupts thedesmoplastic and immunosuppressive TME, and upregulates PD-L1 and ENT1, renderingPDAC eradicable by immunochemotherapy.
DOI: 10.1016/j.cell.2021.07.020
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00879-5