Restoration of CD4 +T helper cells without modulating the hepatic inflammatory pattern is not sufficient to prevent HCC

M. Manjili, Madison Isbell, Nicholas Koelsch, F. Mirshahi, Chubquing Guo, M. Idowu, Dana Austin, C. Gelber, Xiang-Yang Wang, A. Sanyal
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Abstract

Recent studies suggest that progression of nonalcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC) is associated with a decreased frequency of the hepatic CD4 +T cells, as well as a predominance of the inflammatory immunological pattern. To determine whether the inhibition of chronic inflammation could prevent the progression of NAFLD to HCC, we used a novel LRP-1 agonistic peptide, SP16, during a progressive NAFLD in an animal model of NAFLD, i.e., DIAMOND mice. Tumor progression, circulating inflammatory cytokines as well as the hepatic immune cells were analyzed using 44-plex cytokine array and multi-color flow cytometry. Although SP16 restored the hepatic CD4 +T cells and slightly increased Th2 subset, it failed to modulate the CD4 +Th1 dominant pattern in the liver or prevent HCC. These data suggest that the hepatic immune pattern, which could produce a collective function independent from its cellular components, is more important than CD4 +T cell recovery during disease progression. Our data also suggest that administration of SP16 very early during NAFLD could shift a predominant Th1 pattern towards an equilibrium Th1=Th2=Th17 pattern which has been found to protect DIAMOND mice from from the progression of NAFLD to HCC. Future studies will determine if modulation of the inflammatory immune response by SP16 when administered early during NAFLD progression will prevent HCC. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under Award No. W81XWH2210793, Massey Cancer Center Multi-Investigator Award, grant number 2017-MIP-02, NIH R01DK105961, and VA Merit Award 1I01BX003275. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Department of Defense. Services and products in support of the research project were generated by the Virginia Commonwealth University Flow Cytometry Shared Resource, supported, in part, with funding from NIH-NCI Cancer Center Support Grant P30 CA016059.
在不调节肝脏炎症模式的情况下恢复CD4 +T辅助细胞不足以预防HCC
最近的研究表明,非酒精性脂肪性肝病(NAFLD)向肝细胞癌(HCC)的进展与肝脏CD4 +T细胞频率降低以及炎症免疫模式的优势相关。为了确定慢性炎症的抑制是否可以阻止NAFLD向HCC的发展,我们在NAFLD动物模型(即DIAMOND小鼠)的进展性NAFLD中使用了一种新的LRP-1激动肽SP16。采用44-plex细胞因子阵列和多色流式细胞术分析肿瘤进展、循环炎症因子和肝脏免疫细胞。虽然SP16恢复了肝脏CD4 +T细胞,并轻微增加了Th2亚群,但它不能调节肝脏中CD4 +Th1的显性模式或预防HCC。这些数据表明,在疾病进展过程中,肝脏免疫模式可以产生独立于其细胞成分的集体功能,比CD4 +T细胞恢复更重要。我们的数据还表明,在NAFLD早期给药SP16可以将主要的Th1模式转变为平衡的Th1=Th2=Th17模式,这已经被发现可以保护DIAMOND小鼠免于NAFLD向HCC的进展。未来的研究将确定在NAFLD进展早期使用SP16来调节炎症免疫反应是否会预防HCC。这项工作得到了卫生事务助理国防部长办公室通过乳腺癌研究项目的支持。W81XWH2210793,梅西癌症中心多研究者奖,资助号2017-MIP-02, NIH R01DK105961, VA优秀奖1I01BX003275。观点、解释、结论和建议是作者的观点,不一定得到美国国防部的认可。支持该研究项目的服务和产品由弗吉尼亚联邦大学流式细胞术共享资源提供,部分由NIH-NCI癌症中心支持基金P30 CA016059资助。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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