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在接受免疫治疗的HCC患者中,NASH限制了抗瘤监测

Dominik Pfister^1,2, Nicolás Gonzalo Núñez³, Roser Pinyol⁴

¹Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.

|March 25, 2021

概括

由非酒精性脂肪肝炎 (NASH) 引起的肝细胞癌可能对免疫治疗没有反应. 与NASH相关的T细胞损害了免疫监测,这表明需要根据HCC原因对患者进行分层.

科学领域:

免疫学
肝病学
癌症学

背景情况:

肝细胞癌 (HCC) 由病毒或非病毒原因引起,非酒精性脂肪肝炎 (NASH) 是一个重要的驱动因素.
免疫疗法对HCC治疗具有前景,但缺乏患者分层和最佳反应预测的生物标志物.
了解T细胞在NASH相关的HCC中的作用对于开发有效的治疗策略至关重要.

研究的目的:

研究NASH受影响的肝脏中CD8+T细胞的积累和激活以及它们在HCC发育中的作用.
在临床前模型中评估计划死亡-1 (PD1) 向免疫治疗的疗效.
确定非病毒性病因,特别是NASH对患者对PD1/ PDL1抑制剂的反应的影响.

主要方法:

在NASH受影响的肝脏和HCC模型中分析CD8+T细胞表型 (PD1+,CXCR6+,TOX+,TNF+).
在临床前NASH- HCC模型中给予抗PD1免疫疗法以评估瘤回归和免疫细胞扩张.
用PD1/ PDL1抑制剂治疗的晚期HCC患者的临床试验数据和队列研究的元分析.

主要成果:

在NASH受影响的肝脏中观察到CD8+PD1+ T细胞逐渐累积.
在NASH- HCC模型中,抗PD1治疗扩大了CD8+PD1+T细胞,但损害了瘤回归,增加了HCC的发病率和大小.
与其他HCC病因相比,非病毒性HCC,特别是NASH- HCC的抗PD1/ PDL1治疗的存活率降低.

结论:

在NASH中异常的CD8+T细胞激活有助于HCC的发展,并损害免疫监测,而不是加强它.
由于与NASH相关的异常T细胞反应,非病毒性HCC,特别是NASH- HCC可能对当前的免疫治疗反应较差.
根据病因因素对HCC患者进行分层是优化免疫疗法的必要条件,并改善患者的治疗结果.

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