Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy,Cell

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Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy
Cell ( IF 64.5 ) Pub Date : 2021-08-12 , DOI: 10.1016/j.cell.2021.07.020
Kazuhiro Koikawa ₁ , Shin Kibe ₂ , Futoshi Suizu ₃ , Nobufumi Sekino ₄ , Nami Kim ₅ , Theresa D Manz ₆ , Benika J Pinch ₆ , Dipikaa Akshinthala ₇ , Ana Verma ₈ , Giorgio Gaglia ₈ , Yutaka Nezu ₉ , Shizhong Ke ₄ , Chenxi Qiu ₄ , Kenoki Ohuchida ₁₀ , Yoshinao Oda ₁₁ , Tae Ho Lee ₁₂ , Babara Wegiel ₁₃ , John G Clohessy ₁₄ , Nir London ₁₅ , Sandro Santagata ₈ , Gerburg M Wulf ₇ , Manuel Hidalgo ₇ , Senthil K Muthuswamy ₇ , Masafumi Nakamura ₁₀ , Nathanael S Gray ₁₆ , Xiao Zhen Zhou ₄ , Kun Ping Lu ₄

Affiliation

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.
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; Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, 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; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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.
Department of Cancer Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, 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.
Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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.
Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
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; Division of Surgical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Surgery, 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; Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Department of Chemical and Structural Biology, The Weizmann Institute of Science, Rehovot, 7610001, Israel.
Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.

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.

中文翻译：

靶向 Pin1 通过与免疫化学疗法的协同作用使胰腺癌得以根除

胰腺导管腺癌 (PDAC) 的特点是对当前治疗的耐药性臭名昭著，这归因于固有的肿瘤异质性和高度促纤维增生和免疫抑制性肿瘤微环境 (TME)。独特的脯氨酸异构酶 Pin1 调节多种癌症通路，但其在 TME 和癌症免疫治疗中的作用尚不清楚。在这里，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，并且与 PDAC 患者的不良生存率相关。使用临床可用药物靶向 Pin1，通过在不同模型系统中与抗 PD-1 和吉西他滨协同作用，诱导完全消除或持续缓解侵袭性 PDAC。机械地，Pin1 通过作用于 CAF 驱动促纤维增生和免疫抑制 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，Pin1 抑制同时阻断多种癌症通路，破坏促纤维增生和免疫抑制 TME，并上调 PD-L1 和 ENT1，使 PDAC 可通过免疫化学疗法根除。

更新日期：2021-09-02

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