Steatohepatitis Impairs T-cell-Directed Immunotherapies Against Liver Tumors in Mice.
Steatohepatitis Impairs T-cell-Directed Immunotherapies Against Liver Tumors in Mice.
复制标题
DOI：
10.1053/j.gastro.2020.09.031
复制
发表时间：
2021-01
期刊：
影响因子：
29.4
通讯作者：
Greten TF
中科院分区：
文献类型：
--
作者：
Heinrich B;Brown ZJ;Diggs LP;Vormehr M;Ma C;Subramanyam V;Rosato U;Ruf B;Walz JS;McVey JC;Wabitsch S;Fu Q;Yu SJ;Zhang Q;Lai CW;Sahin U;Greten TF
非酒精性脂肪性肝炎导致肝脏CD4+T细胞丧失，促进肿瘤生长。肝脏是各种恶性肿瘤最常见的远处转移部位，其中许多对免疫治疗有反应。我们研究了脂肪性肝炎对免疫治疗剂抗小鼠肝肿瘤疗效的影响。用蛋氨酸和胆碱缺乏饲料或L氨基酸限定饲料喂养C57BL/6NCr1或BALB/c AnNCr小鼠诱发脂肪性肝炎。小鼠肝内或皮下注射B16黑色素瘤和CT26结肠癌细胞，然后在注射肿瘤细胞后第3、7和10天静脉注射mRNA疫苗(M30)或腹腔注射抗OX40抗体(AOX40)。检测肿瘤生长情况，并用流式细胞仪分析肿瘤组织中的免疫细胞。小鼠给予N-乙酰半胱氨酸(NAC)以防止肝脏中CD4+T细胞的丢失。给予M30和aOX40可抑制常规饮食小鼠肝内注射B16或CT26细胞所产生的肿瘤生长。然而，在饮食诱导脂肪性肝炎(MCD或CDAA)的小鼠中，M30和/或aOX40并不减缓B16或CT26细胞产生的肝肿瘤的生长。脂肪性肝炎不影响M30减缓皮下B16肿瘤生长的能力。在脂肪性肝炎小鼠中，服用NAC可以防止CD4+T细胞的损失，M30和aOX40能够减缓肝肿瘤的生长。对肝肿瘤的流式细胞仪分析显示，患有脂肪性肝炎的小鼠与非脂肪性肝炎的小鼠相比，CD4+T细胞和效应记忆细胞减少，脂肪性肝炎降低了免疫治疗药物如M30和aOX40通过减少CD4+T细胞和效应记忆细胞的肿瘤侵袭而抑制肿瘤肝脏生长的能力。NAC可恢复肿瘤中T细胞的数量，并增加M30和aOX40减缓小鼠肿瘤生长的能力。
Non-alcoholic steatohepatitis causes loss of hepatic CD4+ T cells and promotes tumor growth. The liver is the most common site of distant metastases from a variety of malignancies, many of which respond to immunotherapy. We investigated the effects of steatohepatitis on the efficacy of immunotherapeutic agents against liver tumors in mice. Steatohepatitis was induced by feeding C57BL/6NCrl or BALB/c AnNCr mice a methionine and choline-deficient diet (MCD) or a choline-deficient L-amino acid-defined diet (CDAA). Mice were given intrahepatic or subcutaneous injections of B16 melanoma and CT26 colon cancer cells, followed by given intravenous injections of mRNA vaccine (M30) or intraperitoneal injections of an antibody against OX40 (aOX40) on days 3, 7, and 10 after injection of the tumor cells. We measured tumor growth and analyzed immune cells in tumor tissues by flow cytometry. Mice were given N-acetylcysteine (NAC) to prevent loss of CD4+ T cells from liver. Administration of M30 and aOX40 inhibited growth of tumors from intrahepatic injections of B16 or CT26 cells in mice on regular diet. However, M30 and/or aOX40 did not slow growth of liver tumors from B16 or CT26 cells in mice with diet-induced steatohepatitis (MCD or CDAA). Steatohepatitis did not affect the ability of M30 to slow growth of subcutaneous B16 tumors. In mice with steatohepatitis given NAC, which prevents loss of CD4+ T cells, M30 and aOX40 were able slow growth of hepatic tumors. Flow cytometry analysis of liver tumors revealed reduced CD4+ T cells and effector memory cells in mice with vs without steatohepatitis Steatohepatitis reduces the abilities of immunotherapeutic agents such as M30 and aOX40 to inhibit tumor liver growth by reducing tumor infiltration by CD4+ T cells and effector memory cells. NAC restores T-cell numbers in tumors and increases the ability of M30 and aOX40 to slow tumor growth in mice.
登录
查看更多内容
影响因子：
--
作者：
Budczies J;von Winterfeld M;Klauschen F;Bockmayr M;Lennerz JK;Denkert C;Wolf T;Warth A;Dietel M;Anagnostopoulos I;Weichert W;Wittschieber D;Stenzinger A
通讯作者：
Stenzinger A
影响因子：
64.8
作者：
Kang, Tae-Won;Yevsa, Tetyana;Zender, Lars
通讯作者：
Zender, Lars
DOI：
10.1046/j.1440-1746.2003.03198.x
发表时间：
2003-11-01
影响因子：
4.1
作者：
Kirsch, R;Clarkson, V;Hall, PD
通讯作者：
Hall, PD
DOI：
10.1007/s00262-018-2190-4
发表时间：
2018-08
期刊：
Cancer immunology, immunotherapy : CII
影响因子：
--
作者：
Brown ZJ;Yu SJ;Heinrich B;Ma C;Fu Q;Sandhu M;Agdashian D;Zhang Q;Korangy F;Greten TF
通讯作者：
Greten TF
影响因子：
64.5
作者：
Buck MD;Sowell RT;Kaech SM;Pearce EL
通讯作者：
Pearce EL