靶向Pin1可通过与免疫化疗协同作用根除胰腺癌。
Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy.
作者信息
Koikawa Kazuhiro, Kibe Shin, Suizu Futoshi, Sekino Nobufumi, Kim Nami, Manz Theresa D, Pinch Benika J, Akshinthala Dipikaa, Verma Ana, Gaglia Giorgio, Nezu Yutaka, Ke Shizhong, Qiu Chenxi, Ohuchida Kenoki, Oda Yoshinao, Lee Tae Ho, Wegiel Babara, Clohessy John G, London Nir, Santagata Sandro, Wulf Gerburg M, Hidalgo Manuel, Muthuswamy Senthil K, Nakamura Masafumi, Gray Nathanael S, Zhou Xiao Zhen, Lu Kun Ping
机构信息
Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
出版信息
Cell. 2021 Sep 2;184(18):4753-4771.e27. doi: 10.1016/j.cell.2021.07.020. Epub 2021 Aug 12.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by notorious resistance to current therapies attributed to inherent tumor heterogeneity and highly desmoplastic and immunosuppressive tumor microenvironment (TME). Unique proline isomerase Pin1 regulates multiple cancer pathways, but its role in the TME and cancer immunotherapy is unknown. Here, we find that Pin1 is overexpressed both in cancer cells and cancer-associated fibroblasts (CAFs) and correlates with poor survival in PDAC patients. Targeting Pin1 using clinically available drugs induces complete elimination or sustained remissions of aggressive PDAC by synergizing with anti-PD-1 and gemcitabine in diverse model systems. Mechanistically, Pin1 drives the desmoplastic and immunosuppressive TME by acting on CAFs and induces lysosomal degradation of the PD-1 ligand PD-L1 and the gemcitabine transporter ENT1 in cancer cells, besides activating multiple cancer pathways. Thus, Pin1 inhibition simultaneously blocks multiple cancer pathways, disrupts the desmoplastic and immunosuppressive TME, and upregulates PD-L1 and ENT1, rendering PDAC eradicable by immunochemotherapy.
胰腺导管腺癌（PDAC）的特点是对当前治疗具有显著抗性，这归因于其内在的肿瘤异质性以及高度促结缔组织增生和免疫抑制的肿瘤微环境（TME）。独特的脯氨酸异构酶Pin1调节多种癌症通路，但其在肿瘤微环境和癌症免疫治疗中的作用尚不清楚。在此，我们发现Pin1在癌细胞和癌症相关成纤维细胞（CAF）中均过表达，且与PDAC患者的不良生存相关。在多种模型系统中，使用临床可用药物靶向Pin1可通过与抗PD-1和吉西他滨协同作用，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驱动促结缔组织增生和免疫抑制的肿瘤微环境，并诱导癌细胞中PD-1配体PD-L1和吉西他滨转运体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，破坏促结缔组织增生和免疫抑制的肿瘤微环境，并上调PD-L1和ENT1，使免疫化疗能够根除PDAC。
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