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通过与免疫化学疗法的协同作用,向Pin1可以消除胰腺癌

Kazuhiro Koikawa¹, Shin Kibe², Futoshi Suizu³

¹Division 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.

|August 13, 2021

概括

通过向瘤微环境和关键癌细胞通路,抑制Pin1可以克服胰腺癌的抵抗力. 这种方法与免疫疗法和化疗相协作,可有效治疗胰腺管腺癌.

科学领域:

癌症学
癌症免疫学
分子生物学

背景情况:

胰腺管腺癌 (PDAC) 由于瘤异质性和抑制瘤微环境 (TME) 而显著抵抗治疗.
林异构酶Pin1在PDAC的TME中的作用及其在癌症免疫治疗中的潜力在很大程度上尚未被探索.

研究的目的:

研究PIN1在PDAC进展中的作用及其对瘤微环境的影响.
评估Pin1抑制与现有PDAC治疗的治疗潜力.

主要方法:

在PDAC患者样本中分析Pin1表达和与生存的相关性.
使用临床上可用的Pin1抑制剂与抗PD-1治疗和gemcitabine相结合的体外和体内研究.
机制研究以阐明Pin1在癌症相关纤维细胞 (CAF),PD-L1和ENT1调节中的作用.

主要成果:

在PDAC细胞和CAF中过度表达Pin1,与患者的存活率较低相关.
在临床前模型中,Pin1抑制与抗PD-1和gemcitabine结合导致瘤完全消除或持续缓解.
抑制Pin1会破坏脱质和免疫抑制的TME,提高PD- L1和gemcitabine输送器ENT1的调节,并抑制多种癌症途径.

结论:

Pin1是PDAC的攻击性表型和治疗耐药性的关键驱动因素.
通过调节TME并增强免疫化学疗法的有效性,针对PIN1提供了一种有希望的策略来克服PDAC耐药性.
抑制Pin1使PDAC易于通过联合免疫化学疗法消除.

关键词:

标签1 癌症免疫逃避与癌症相关的纤维细胞化学疗法组合治疗免疫检查点治疗胰腺癌针对性的治疗瘤免疫微环境瘤微环境

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