癌症研究
医学
黑色素瘤
转移
肿瘤微环境
免疫系统
免疫检查点
免疫疗法
肿瘤浸润淋巴细胞
背向效应
肿瘤科
癌症
FOXP3型
作者
Lujun Shen,Ying Wu,Han Qi,Jietian Jin,Fei Cao,Lin Xie,Shuanggang Chen,Yuanzhong Yang,Tao Huang,Ze Song,Qifeng Chen,Yinqi Zhang,Jinqing Mo,Dan Dan Li,Xizhi Wen,Xiaoshi Zhang,Weijun Fan
摘要
Purpose: Metastatic uveal melanoma is a lethal disease with no standard treatment. Here we studied a case with metastatic uveal melanoma (UVM) and had unexpected contrast response to PD-1 inhibitor in liver metastasis.
Experimental design: Whole exome sequencing, RNA sequencing, and immunohistochemistry (IHC) and multiplex immunofluorescence imaging (MII) were conducted on the biopsied samples of intrahepatic lesions with differential responses. Combined bioinformatics analysis of the patient and public dataset including The Cancer Genome Atlas uveal melanoma (TCGA-UVM) cohort and NCBI Gene Expression Omnibus (GEO) cohorts were performed.
Results: The differences in somatic mutations and tumor mutation burden between complete response (CR) and progressive disease (PD) lesion of the patient were small. IHC suggested both CR and PD lesions were PD-L1 negative and had diffuse CD8+ TILs and Foxp3+ TILs infiltration. Using ImmuCellAI, an advanced tool to estimate the abundance of 24 immune cells from gene expression dataset, PD lesion was found to have more than two times the abundance of inducible regulatory T cell (iTreg) compared with the CR lesion; the abundance of nTreg were similar. Based on GEO datasets, high abundance of iTreg was found able to predict poor response to PD-1 inhibitor and was correlated with unfavorable prognosis of advanced melanoma patients receiving PD-1 blockade therapy; high iTreg also correlates with unfavorable prognosis in TCGA-UVM cohort. Bioinformatic analysis of transcriptome data of this patient and TCGA-UVM cohort revealed iTreg may negatively impact on PD-1 blockade therapy through the IL-10-PRDM1 axis, which is confirmed by MII under microscope.
Conclusion: This study provides an insight into the suppressive impact of iTreg on the efficacy of PD-1 blockade therapy and will facilitate the development of novel treatment against its tolerance in the future.
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