经动脉栓塞调节大鼠模型中靶区和非靶区肝细胞癌内的免疫反应。

Transarterial Embolization Modulates the Immune Response within Target and Nontarget Hepatocellular Carcinomas in a Rat Model.

作者信息

Tischfield David J, Gurevich Alexey, Johnson Omar, Gatmaytan Isabela, Nadolski Gregory J, Soulen Michael C, Kaplan David E, Furth Emma, Hunt Stephen J, Gade Terence P F

机构信息

From the Penn Image-Guided Interventions Laboratory (D.J.T., A.G., O.J., I.G., G.J.N., S.J.H., T.P.F.G.), Department of Radiology (D.J.T., O.J., G.J.N., M.C.S., S.J.H., T.P.F.G.), and Department of Pathology (E.F.), Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104; Division of Gastroenterology and Hepatology (D.E.K.) and Department of Cancer Biology (T.P.F.G.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa; and Gastroenterology Section, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pa (D.E.K.).

出版信息

Radiology. 2022 Apr;303(1):215-225. doi: 10.1148/radiol.211028. Epub 2022 Jan 11.

DOI:10.1148/radiol.211028

PMID:35014906

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8962821/

Abstract

Background Transarterial embolization (TAE) is the most common treatment for hepatocellular carcinoma (HCC); however, there remain limited data describing the influence of TAE on the tumor immune microenvironment. Purpose To characterize TAE-induced modulation of the tumor immune microenvironment in a rat model of HCC and identify factors that modulate this response. Materials and Methods TAE was performed on autochthonous HCCs induced in rats with use of diethylnitrosamine. CD3, CD4, CD8, and FOXP3 lymphocytes, as well as programmed cell death protein ligand-1 () expression, were examined in three cohorts: tumors from rats that did not undergo embolization (control), embolized tumors (target), and nonembolized tumors from rats that had a different target tumor embolized (nontarget). Differences in immune cell recruitment associated with embolic agent type (tris-acryl gelatin microspheres [TAGM] vs hydrogel embolics) and vascular location were examined in rat and human tissues. A generalized estimating equation model and , Mann-Whitney , and χ tests were used to compare groups. Results Cirrhosis-induced alterations in CD8, CD4, and CD25/CD4 lymphocytes were partially normalized following TAE (CD8: 38.4%, CD4: 57.6%, and CD25/CD4: 21.1% in embolized liver vs 47.7% [ = .02], 47.0% [ = .01], and 34.9% [ = .03], respectively, in cirrhotic liver [36.1%, 59.6%, and 4.6% in normal liver]). Embolized tumors had a greater number of CD3, CD4, and CD8 tumor-infiltrating lymphocytes relative to controls (191.4 cells/mm vs 106.7 cells/mm [ = .03]; 127.8 cells/mm vs 53.8 cells/mm [ < .001]; and 131.4 cells/mm vs 78.3 cells/mm [ = .01]) as well as a higher expression score (4.1 au vs 1.9 au [ < .001]). A greater number of CD3, CD4, and CD8 lymphocytes were found near TAGM versus hydrogel embolics (4.1 vs 2.0 [ = .003]; 3.7 vs 2.0 [ = .01]; and 2.2 vs 1.1 [ = .03], respectively). The number of lymphocytes adjacent to embolics differed based on vascular location (17.9 extravascular CD68 peri-TAGM cells vs 7.0 intravascular [ < .001]; 6.4 extravascular CD68 peri-hydrogel embolic cells vs 3.4 intravascular [ < .001]). Conclusion Transarterial embolization-induced dynamic alterations of the tumor immune microenvironment are influenced by underlying liver disease, embolic agent type, and vascular location. © RSNA, 2022 See also the editorials by Kennedy et al and by White in this issue.

摘要

背景经动脉栓塞术（TAE）是肝细胞癌（HCC）最常用的治疗方法；然而，关于TAE对肿瘤免疫微环境影响的数据仍然有限。目的描述TAE在HCC大鼠模型中诱导的肿瘤免疫微环境调节，并确定调节这种反应的因素。材料与方法对用二乙基亚硝胺诱导的大鼠自发性HCC进行TAE。在三个队列中检测CD3、CD4、CD8和FOXP3淋巴细胞以及程序性细胞死亡蛋白配体1（）的表达：未接受栓塞的大鼠的肿瘤（对照）、栓塞的肿瘤（靶标）以及来自对不同靶标肿瘤进行栓塞的大鼠的未栓塞肿瘤（非靶标）。在大鼠和人体组织中研究与栓塞剂类型（三丙烯酸明胶微球[TAGM]与水凝胶栓塞剂）和血管位置相关的免疫细胞募集差异。使用广义估计方程模型以及Mann-Whitney检验和χ²检验对组间进行比较。结果 TAE后，肝硬化诱导的CD8、CD4和CD25/CD4淋巴细胞改变部分恢复正常（栓塞肝脏中CD8为38.4%、CD4为57.6%、CD25/CD4为21.1%，而肝硬化肝脏中分别为47.7%[P = .02]、47.0%[P = .01]和34.9%[P = .03] [正常肝脏中为36.1%、59.6%和4.6%]）。相对于对照组，栓塞肿瘤中浸润的CD3、CD4和CD8肿瘤淋巴细胞数量更多（191.4个细胞/mm² 对106.7个细胞/mm² [P = .03]；127.8个细胞/mm² 对53.8个细胞/mm² [P < .001]；131.4个细胞/mm² 对78.3个细胞/mm² [P = .01]），并且表达评分更高（4.1任意单位对1.9任意单位 [P < .001]）。与水凝胶栓塞剂相比，在TAGM附近发现更多的CD3、CD4和CD8淋巴细胞（分别为4.1对2.0 [P = .003]；3.7对2.0 [P = .01]；2.2对1.1 [P = .03]）。与栓塞剂相邻的淋巴细胞数量因血管位置而异（血管外17.9个CD68阳性的TAGM周围细胞对血管内7.0个 [P < .001]；血管外6.4个CD68阳性的水凝胶栓塞剂周围细胞对血管内3.4个 [P < .001]）。结论经动脉栓塞术诱导的肿瘤免疫微环境动态改变受潜在肝脏疾病、栓塞剂类型和血管位置影响。© RSNA, 2022 另见本期Kennedy等人和White的社论。