Tumor Fibroblast-Derived FGF2 Regulates Expression of SPRY1 in Esophageal Tumor-Infiltrating T Cells and Plays a Role in T-cell Exhaustion
Tumor Fibroblast-Derived FGF2 Regulates Expression of SPRY1 in Esophageal Tumor-Infiltrating T Cells and Plays a Role in T-cell Exhaustion
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肿瘤成纤维细胞衍生的 FGF2 调节食管肿瘤浸润 T 细胞中 SPRY1 的表达并在 T 细胞耗竭中发挥作用
DOI：
10.1158/0008-5472.can-20-1542
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发表时间：
2020-12-15
期刊：
影响因子：
11.2
通讯作者：
Guan, Xin-Yuan
中科院分区：
文献类型：
--
作者：
Chen, Qing-yun;Li, Yi-ni;Guan, Xin-Yuan
t细胞衰竭最初在小鼠慢性感染中被发现，随后在癌症患者中被描述。尽管在癌症中T细胞耗竭（T- ex）的独特特征已经得到了很好的研究，但癌症中T细胞耗竭的分子机制尚不完全清楚。使用单细胞RNA测序，我们在这里报告食管癌中的T-EX细胞比以前阐明的更具异质性。Sprouty RTK信号拮抗剂1 （SPRY1）在两个精疲力尽的CD8(+) T细胞亚群中显著富集。当过度表达时，SPRY1通过与CBL（一种ZAP-70酪氨酸磷酸化的负调节因子）相互作用而损害t细胞的激活。来自肿瘤免疫估计资源的数据显示食管癌中FGF2和SPRY1的表达有很强的相关性。FGF2在食管癌组织成纤维细胞中明显高表达，并与较差的总生存率相关。体外给药FGF2显著上调CD8(+) T细胞中SPRY I的表达，并减弱T细胞受体触发的CD8(+) T细胞活化。小鼠肿瘤模型证实，成纤维细胞中过表达FGF2可显著上调T-EX细胞中SPRY I的表达，损害t细胞的细胞毒活性，促进肿瘤生长。因此，这些发现表明FGF2是SPRY I表达的重要调节因子，参与了食管癌中CD8(+) T细胞功能失调状态的建立。意义：这些发现揭示了FGF2是SPRY1表达的重要调节因子，参与了CD8(+) T细胞功能失调状态的建立，提示抑制FGF2在ESCC中具有潜在的临床价值。
T-cell exhaustion was initially identified in chronic infection in mice and was subsequently described in humans with cancer. Although the distinct signature of exhausted T (T-EX) cells in cancer has been well investigated, the molecular mechanism of T-cell exhaustion in cancer is not fully understood. Using single-cell RNA sequencing, we report here that T-EX cells in esophageal cancer are more heterogeneous than previously clarified. Sprouty RTK signaling antagonist 1 (SPRY1) was notably enriched in two subsets of exhausted CD8(+) T cells. When overexpressed, SPRY1 impaired T-cell activation by interacting with CBL, a negative regulator of ZAP-70 tyrosine phosphorylation. Data from the Tumor Immune Estimation Resource revealed a strong correlation between FGF2 and SPRY1 expression in esophageal cancer. High expression of FGF2 was evident in fibroblasts from esophageal cancer tissue and correlated with poor overall survival. In vitro administration of FGF2 significantly upregulated expression of SPRY I in CD8(+) T cells and attenuated T-cell receptor-triggered CD8(+) T-cell activation. A mouse tumor model confirmed that overexpression of FGF2 in fibroblasts significantly upregulated SPRY I expression in T-EX cells, impaired T-cell cytotoxic activity, and promoted tumor growth. Thus, these findings identify FGF2 as an important regulator of SPRY I expression involved in establishing the dysfunctional state of CD8(+) T cells in esophageal cancer.Significance: These findings reveal FGF2 as an important regulator of SPRY1 expression involved in establishing the dysfunctional state of CD8(+) T cells and suggest that inhibition of FGF2 has potential clinical value in ESCC.[GRAPHICS].