Multi Organ Transplant Program and Division of Gastroenterology, University Health Network and University of Toronto, Toronto, Canada.
Scripps Clinic Bio-Repository & Transplantation Research, Scripps Clinic & Green Hospital, La Jolla, California, USA.
Cancer Med. 2023 Feb;12(4):5150-5157. doi: 10.1002/cam4.5271. Epub 2022 Oct 7.
Long-term survival of transplant recipients is significantly impacted by malignancy. We aimed to determine whether calcineurin inhibitor (CNI)-treated recipients converted to and weaned off molecular target of rapamycin inhibitor (mTOR-I) therapy have favorable changes in their molecular profiles in regard to malignancy risk. We performed gene expression profiling from liver biopsy and blood (PBMC) specimens followed by network analysis of key dysregulated genes, associated diseases and disorders, molecular and cellular functions using IPA software. Twenty non-immune, non-viremic patients were included, and 8 of them achieved tolerance. Two comparisons were performed: (1) tolerance time point vs tacrolimus monotherapy and (2) tolerance time point vs sirolimus monotherapy. Upon achieving tolerance, IPA predicted significant activation of DNA damage response (p = 5.40e-04) and inhibition of DNA replication (p = 7.56e-03). Conversion from sirolimus to tolerance showed decrease in HCC (p = 1.30e-02), hepatic steatosis (p = 5.60e-02) and liver fibrosis (p = 2.91e-02) associated genes. In conclusion, this longitudinal study of patients eventually achieving tolerance reveals an evolving molecular profile associated with decreased cancer risk and improved hepatic steatosis and liver fibrosis. This provides a biological rationale for attempting conversion to mTOR-I therapy and tolerance following liver transplantation particularly in patients at higher risk of cancer incidence and progression post-transplant.
移植受者的长期生存受到恶性肿瘤的显著影响。我们旨在确定接受钙调神经磷酸酶抑制剂（CNI）治疗的受者是否转为并逐渐减少雷帕霉素抑制剂（mTOR-I）治疗后，其恶性肿瘤风险相关的分子谱是否有有利变化。我们对肝活检和血液（PBMC）标本进行了基因表达谱分析，然后使用 IPA 软件对关键失调基因、相关疾病和障碍、分子和细胞功能进行了网络分析。共纳入 20 例非免疫、非病毒血症患者，其中 8 例达到了耐受。进行了两种比较：（1）耐受时间点与他克莫司单药治疗的比较；（2）耐受时间点与西罗莫司单药治疗的比较。达到耐受时，IPA 预测 DNA 损伤反应明显激活（p=5.40e-04）和 DNA 复制抑制（p=7.56e-03）。从西罗莫司转为耐受时，与 HCC（p=1.30e-02）、肝脂肪变性（p=5.60e-02）和肝纤维化（p=2.91e-02）相关的基因减少。总之，这项最终达到耐受的患者的纵向研究揭示了与癌症风险降低以及改善肝脂肪变性和肝纤维化相关的不断演变的分子谱。这为尝试在肝移植后转为 mTOR-I 治疗和耐受提供了生物学依据，特别是在移植后癌症发病率和进展风险较高的患者中。
