Multiple Immune-Suppressive Mechanisms in Fibrolamellar Carcinoma.
Multiple Immune-Suppressive Mechanisms in Fibrolamellar Carcinoma.
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DOI：
10.1158/2326-6066.cir-18-0499
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发表时间：
2019-05
影响因子：
10.1
通讯作者：
中科院分区：
文献类型：
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作者：
纤维板层癌（FLC）是一种罕见的肝癌，影响青少年和年轻人。FLC最有效的治疗方法是手术切除，但对于复发或不可切除的FLC患者尚无标准化的系统治疗。作为了解FLC免疫微环境的第一步，我们研究了与CD 8+细胞毒性T淋巴细胞密度相关的靶向免疫检查点途径PD-1、PD-L1、B7-H3、IDO-1和LAG 3。使用IHC染色分析32份FLC肿瘤标本的PD-L1、CD 8、PD-1、IDO、LAG 3和B7-H3。63%的FLC病例显示肿瘤细胞上有膜性PD-L1表达，近70%的病例显示PD-L1+肿瘤浸润淋巴细胞和肿瘤相关巨噬细胞（TIL/TAM）。骨髓来源的细胞似乎是PD-L1+肿瘤浸润免疫细胞的主要成分。40%的病例在肿瘤区显示B7-H3表达，91%的病例在TIL和TAM中显示B7-H3表达。IDO和PD-1在肿瘤界面区表达最高。肿瘤细胞上的B7-H3或IDO表达与较高的CD 8 + T细胞密度显著相关。总之，高比例的FLC病例在适应性免疫耐药模式中显示PD-1、PD-L1、B7-H3和IDO的稳健表达。我们的研究结果为在FLC中靶向这些不同的免疫检查点轴提供了进一步的基础。
Fibrolamellar carcinoma (FLC) is a rare type of liver cancer that affects adolescents and young adults. The most effective treatment for FLC is surgical resection, but no standardized systemic therapy exists for patients with recurrent or unresectable FLC. As a first step to understand the immune microenvironment of FLC, we investigated targetable immune-checkpoint pathways, PD-1, PD-L1, B7-H3, IDO-1, and LAG3, in relation to CD8+ cytotoxic T-lymphocyte density. Thirty-two FLC tumor specimens were analyzed using IHC staining for PD-L1, CD8, PD-1, IDO, LAG3, and B7-H3. Sixty-three percent of FLC cases demonstrated membranous PD-L1 expression on tumor cells, and almost 70% of cases demonstrated PD-L1+ tumor-infiltrating lymphocytes and tumor-associated macrophages (TIL/TAM). Myeloid-derived cells appeared to be a major component of PD-L1+ tumor-infiltrating immune cells. Forty percent of the cases showed B7-H3 expression in the tumor zone, with 91% cases showing B7-H3 expression in TILs and TAMs. IDO and PD-1 expression was highest in the tumor interface zone. B7-H3 or IDO expression on tumor cells significantly correlated with higher CD8+ T-cell density. In conclusion, a high proportion of FLC cases showed robust expression of PD-1, PD-L1, B7-H3, and IDO in an adaptive immune-resistance pattern. Our findings provide further basis for targeting these different immune-checkpoint axes in FLC.