Cancer-associated fibroblast senescence and its relation with tumour-infiltrating lymphocytes and PD-L1 expressions in intrahepatic cholangiocarcinoma
Cancer-associated fibroblast senescence and its relation with tumour-infiltrating lymphocytes and PD-L1 expressions in intrahepatic cholangiocarcinoma
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DOI：
10.1038/s41416-021-01569-6
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发表时间：
2021-10-06
影响因子：
8.8
通讯作者：
Baba, Hideo
中科院分区：
文献类型：
--
作者：
Lan, Chuan;Kitano, Yuki;Baba, Hideo
癌症相关成纤维细胞（CAFs）中的CAV1具有促或抗肿瘤作用，这取决于癌症类型。然而，其在肝内癌（ICC）中的作用尚不清楚。因此，本研究旨在探讨ICC患者CAFs中CAV1与肿瘤浸润淋巴细胞（TIL）数量或PD-L1水平的关系。方法连续入组158例ICC患者。采用免疫组化方法分析癌细胞CAFs、CD8 + TILs、Foxp3+ TILs和PD-L1中CAV1的表达水平。评估其与临床病理因素及预后的关系。评估了这些因素之间的相关性。结果CAFs中CAV1表达上调与不良的总生存期（OS） （P < 0.001）和无复发生存期（P = 0.008）相关。临床病理因素与高CA19-9水平（P < 0.001）、肿瘤分期晚期（P = 0.046）和淋巴结转移（P = 0.004）相关。CAV1水平与Foxp3+ TIL数呈正相关（P = 0.01）。CAV1水平与CD8 + TIL数（P = 0.80）、PD-L1水平（P = 0.97）无显著相关性。CD8 + TIL增加和Foxp3+ TIL减少与OS增加相关。在多因素分析中，CAFs中CAV1阳性表达（P = 0.013）和CD8 + TIL减少（P = 0.021）是独立的预后不良因素。结论以CAV1水平为代表的细胞衰老可能是CAFs的标志，并通过Foxp3+ TIL的调控作为ICC的预后指标。caf中的CAV1表达可能是ICC的治疗靶点。
Background Caveolin-1 (CAV1) in cancer-associated fibroblasts (CAFs) has pro- or anti-tumourigenic effect depending on the cancer type. However, its effect in intrahepatic carcinoma (ICC) remains unknown. Therefore, this study aimed to investigate the relationship between CAV1 in CAFs and tumour-infiltrating lymphocyte (TIL) numbers or PD-L1 levels in ICC patients. Methods Consecutive ICC patients (n = 158) were enrolled in this study. The levels of CAV1 in CAFs, CD8 + TILs, Foxp3+ TILs and PD-L1 in cancer cells were analysed using immunohistochemistry. Their association with the clinicopathological factors and prognosis were evaluated. The correlation between these factors was evaluated. Results CAV1 upregulation in CAFs was associated with a poor overall survival (OS) (P < 0.001) and recurrence-free survival (P = 0.008). Clinicopathological factors were associated with high CA19-9 levels (P < 0.001), advanced tumour stage (P = 0.046) and lymph node metastasis (P = 0.004). CAV1 level was positively correlated with Foxp3+ TIL numbers (P = 0.01). There were no significant correlations between CAV1 levels and CD8 + TIL numbers (P = 0.80) and PD-L1 levels (P = 0.97). An increased CD8 + TIL number and decreased Foxp3+ TIL number were associated with an increased OS. In multivariate analysis, positive CAV1 expression in CAFs (P = 0.013) and decreased CD8 + TIL numbers (P = 0.021) were independent poor prognostic factors. Conclusion Cellular senescence, represented by CAV1 levels, may be a marker of CAFs and a prognostic indicator of ICC through Foxp3+ TIL regulation. CAV1 expression in CAFs can be a therapeutic target for ICC.