4-(N)-二十二碳六烯酰基-2',2'-二氟脱氧胞苷作为单一药物在结直肠癌和胰腺癌模型中诱导免疫原性细胞死亡。
4-(N)-Docosahexaenoyl 2', 2'-difluorodeoxycytidine induces immunogenic cell death in colon and pancreatic carcinoma models as a single agent.
机构信息
Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA.
Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
出版信息
Cancer Chemother Pharmacol. 2022 Jan;89(1):59-69. doi: 10.1007/s00280-021-04367-2. Epub 2021 Oct 26.
PURPOSE
Docosahexaenoyl difluorodeoxycytidine (DHA-dFdC) is an amide with potent, broad-spectrum antitumor activity. In the present study, DHA-dFdC's ability to induce immunogenic cell death (ICD) was tested using CT26 mouse colorectal cancer cells, an established cell line commonly used for identifying ICD inducers, as well as Panc-02 mouse pancreatic cancer cells.
METHODS
The three primary surrogate markers of ICD (i.e., calreticulin (CRT) surface translocation, ATP release, and high mobility group box 1 protein (HMGB1) release) were measured in vitro. To confirm DHA-dFdC's ability to induce ICD in vivo, the gold standard mouse vaccination studies were conducted using both CT26 and Panc-02 models. Additionally, the effect of DHA-dFdC on tumor response to anti-programmed cell death protein 1 monoclonal antibody (anti-PD-1 mAb) were tested in mice with pre-established Panc-02 tumors. RNA sequencing experiments were conducted on PANC-1 human pancreatic cancer cells treated with DHA-dFdC, dFdC, or vehicle control in vitro.
RESULTS
DHA-dFdC elicited CRT surface translocation and ATP and HMGB1 release in both cell lines. Immunization of mice with CT26 or Panc-02 cells pretreated with DHA-dFdC prevented or delayed the development of corresponding secondary live challenge tumor. DHA-dFdC enabled Panc-02 tumors to respond to anti-PD-1 mAb. RNA sequencing experiments revealed that DHA-dFdC and dFdC differentially impacted genes related to the KRAS, TP53, and inflammatory pathways, and DHA-dFdC enriched for the unfolded protein response (UPR) compared to control, providing insight into DHA-dFdC's potential mechanism of inducing ICD.
CONCLUSION
DHA-dFdC is a bona fide ICD inducer and can render pancreatic tumors responsive to anti-PD-1 mAb therapy.
目的
二十二碳六烯酸二氟脱氧胞苷（DHA-dFdC）是一种酰胺类化合物，具有强大的广谱抗肿瘤活性。在本研究中，使用 CT26 小鼠结直肠癌细胞和已建立的常用于鉴定 ICD 诱导剂的 Panc-02 小鼠胰腺癌细胞测试了 DHA-dFdC 诱导免疫原性细胞死亡（ICD）的能力。
方法
在体外测量了三种主要的 ICD 替代标志物（即钙网蛋白（CRT）表面易位、ATP 释放和高迁移率族蛋白 1 蛋白（HMGB1）释放）。为了确认 DHA-dFdC 在体内诱导 ICD 的能力，使用 CT26 和 Panc-02 模型进行了标准的小鼠疫苗接种研究。此外，还在已建立的 Panc-02 肿瘤小鼠中测试了 DHA-dFdC 对肿瘤对抗程序性细胞死亡蛋白 1 单克隆抗体（抗 PD-1 mAb）反应的影响。对体外用 DHA-dFdC、dFdC 或载体对照处理的 PANC-1 人胰腺癌细胞进行了 RNA 测序实验。
结果
DHA-dFdC 在两种细胞系中均引起 CRT 表面易位以及 ATP 和 HMGB1 的释放。用 DHA-dFdC 预处理的 CT26 或 Panc-02 细胞免疫接种小鼠可预防或延迟相应的二次活体挑战肿瘤的发展。DHA-dFdC 使 Panc-02 肿瘤对抗 PD-1 mAb 治疗有反应。RNA 测序实验表明，DHA-dFdC 和 dFdC 对与 KRAS、TP53 和炎症途径相关的基因产生了不同的影响，并且与对照相比，DHA-dFdC 使未折叠蛋白反应（UPR）富集，这为 DHA-dFdC 诱导 ICD 的潜在机制提供了见解。
结论
DHA-dFdC 是一种真正的 ICD 诱导剂，可使胰腺肿瘤对抗 PD-1 mAb 治疗有反应。
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