Prognostic Significance of Immune Checkpoints HLA-G/ILT-2/4 and PD-L1 in Colorectal Cancer.
Prognostic Significance of Immune Checkpoints HLA-G/ILT-2/4 and PD-L1 in Colorectal Cancer.
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DOI：
10.3389/fimmu.2021.679090
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发表时间：
2021
影响因子：
7.3
通讯作者：
Lin A
中科院分区：
文献类型：
--
作者：
Chen QY;Chen YX;Han QY;Zhang JG;Zhou WJ;Zhang X;Ye YH;Yan WH;Lin A
免疫检查点抑制剂（ICI）已成为癌症治疗研究的一个有前途的领域。除了众所周知的靶向PD-1/PD-L1的ICI外，HLA-G/ILT-2/-4是相对较新的免疫检查点，已在晚期实体瘤患者的早期临床试验中进行了评估。在这项研究中，HLA-G（n=157），ILT-2/4（n=82），PD-L1（n=70）在上皮细胞粘附分子（EpCAM）阳性结直肠癌（CRC）细胞的表达进行了分析，并评估这些分子的预后意义。在EpCAM+ CRC细胞中，HLA-G、ILT-2、ILT-4和PD-L1的中位百分比分别为14.90%、67.70%、8.55%和80.30%。此外，在它们之间观察到正相关（均p<0.001）。较高水平的这些免疫检查点蛋白与淋巴结转移相关。除了AJCC分期（p=0.001）外，Kaplan-Meier生存分析显示，HLA-G（p=0.041）、ILT-2（p=0.060）、ILT-4（p<0.001）、PD-L1（p=0.012）、HLA-GILT-4（p<0.001）和ILT-2 ILT-4（p<0.001）水平较高与CRC患者生存期较短显著相关。当CRC患者按早期和晚期AJCC分期分层时，HLA-G水平仅与早期疾病分期的CRC患者的生存相关（p=0.024），而ILT-4水平对于早期（p=0.001）和晚期（p=0.020）疾病分期的CRC患者均显着。多变量考克斯回归分析显示，晚期AJCC分期（HR=2.435; p=0.005）和较高的ILT-4水平（HR=2.198; p=0.063）是CRC患者预后不良的独立危险因素。总之，在免疫检查点HLA-G/ILT-2/4和PD-L1中，ILT-4是CRC最重要的预后指标。这一发现表明，免疫治疗策略的组合，如ILT-4阻断，可以改善癌症患者的临床结果。此外，流式细胞术可用作免疫组织化学的可靠且有效的替代方法，用于评估肿瘤病变中表达的免疫检查点蛋白。
Immune checkpoint inhibitors (ICIs) have become a promising area of research for cancer treatment. In addition to the well-known ICIs targeting PD-1/PD-L1, HLA-G/ILT-2/-4 is relatively new immune checkpoint that has been evaluated in early clinical trials in patients with advanced solid tumors. In this study, the expression of HLA-G (n=157), ILT-2/4 (n=82), and PD-L1 (n=70) in epithelial cell adhesion molecule (EpCAM)-positive colorectal cancer (CRC) cells was analyzed by multicolor flow cytometry, and the prognostic significance of these molecules was evaluated. In EpCAM+ CRC cells, the median percentages of HLA-G, ILT-2, ILT-4, and PD-L1 were 14.90%, 67.70%, 8.55% and 80.30%, respectively. In addition, a positive correlation was observed between them (all p<0.001). Higher levels of these immune checkpoint proteins are associated with lymph node metastasis. In addition to the AJCC stage (p=0.001), Kaplan-Meier survival analysis showed that higher levels of HLA-G (p=0.041), ILT-2 (p=0.060), ILT-4 (p<0.001), PD-L1 (p=0.012), HLA-GILT4 (p<0.001) and ILT-2ILT-4 (p<0.001) were significantly associated with shorter survival of CRC patients. When CRC patients were stratified by early and advanced AJCC stages, HLA-G levels were only related to the survival among CRC patients with early disease stage (p=0.024), while ILT-4 levels were significant for both CRC patients with early (p=0.001) and advanced (p=0.020) disease stages. Multivariate cox regression analysis revealed that advanced AJCC stage (HR=2.435; p=0.005) and higher ILT-4 levels (HR=2.198; p=0.063) were independent risk factors for poor outcomes in patients with CRC. In summary, among the immune checkpoints, HLA-G/ILT-2/4 and PD-L1, ILT-4 is the most significant prognostic indicator of CRC. This finding indicated that a combination of immunotherapy strategies, such as ILT-4 blockade, could improve the clinical outcomes in patients with cancer. Moreover, multicolor flow cytometry can be employed as a reliable and efficient, alternative to immunohistochemistry, for evaluating the immune checkpoint proteins expressed in tumor lesions.
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影响因子：
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作者：
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