Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China.
Microbiol Spectr. 2024 May 2;12(5):e0183923. doi: 10.1128/spectrum.01839-23. Epub 2024 Apr 2.
Solid organ transplantation is a crucial treatment for patients who have reached the end stage of heart, lung, kidney, or liver failure. However, the likelihood of developing cancer post-transplantation increases. Additionally, primary malignant tumors remain a major obstacle to the long-term survival of transplanted organs. Therefore, it is essential to investigate effective therapies that can boost the immune system's ability to combat cancer and prevent allograft rejection. We established a mouse orthotopic liver tumor model and conducted allogeneic heterotopic heart transplantation. Various treatments were administered, and survival curves were generated using the Kaplan-Meier method. We also collected graft samples and measured inflammatory cytokine levels in the serum using an inflammatory array. The specificity of the histochemical techniques was tested by staining sections. We administered a combination therapy of phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) dual inhibitor BEZ235 and HN001 to primary liver cancer model mice with cardiac allografts. Consistent with our prior findings, HN001 alleviated the intestinal flora imbalance caused by BEZ235. Our previous research confirmed that the combination of BEZ235 and HN001 significantly prolonged cardiac transplant survival.
We observed that the combination of phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) dual inhibitor BEZ235 and HN001 notably prolonged cardiac transplant survival while also inhibiting the progression of primary liver cancer. The combination therapy was efficacious in treating antitumor immunity and allograft rejection, as demonstrated by the efficacy results. We also found that this phenomenon was accompanied by the regulation of inflammatory IL-6 expression. Our study presents a novel and effective therapeutic approach to address antitumor immunity and prevent allograft rejection.
实体器官移植是治疗心脏、肺、肾或肝功能衰竭终末期患者的关键治疗方法。然而，移植后发生癌症的可能性增加。此外，原发性恶性肿瘤仍然是移植器官长期存活的主要障碍。因此，有必要研究有效的治疗方法，以增强免疫系统对抗癌症和预防同种异体移植排斥的能力。我们建立了小鼠原位肝肿瘤模型，并进行了同种异体异位心脏移植。给予各种治疗，并使用 Kaplan-Meier 方法生成生存曲线。我们还收集了移植物样本，并使用炎症数组测量血清中的炎症细胞因子水平。通过对切片进行染色来测试组织化学技术的特异性。我们对具有心脏同种异体移植物的原发性肝癌模型小鼠给予磷脂酰肌醇 3-激酶/哺乳动物雷帕霉素靶蛋白（PI3K/mTOR）双重抑制剂 BEZ235 和 HN001 的联合治疗。与我们之前的发现一致，HN001 缓解了 BEZ235 引起的肠道菌群失衡。我们之前的研究证实，BEZ235 和 HN001 的联合显著延长了心脏移植的存活时间。
我们观察到，PI3K/mTOR 双重抑制剂 BEZ235 和 HN001 的联合显著延长了心脏移植的存活时间，同时抑制了原发性肝癌的进展。联合治疗在治疗抗肿瘤免疫和同种异体移植排斥方面是有效的，这一疗效结果得到了证实。我们还发现，这种现象伴随着炎症性 IL-6 表达的调节。我们的研究提出了一种新的有效的治疗方法，以解决抗肿瘤免疫和预防同种异体移植排斥。
