泛癌症分析确定 PD-L2 为肿瘤微环境中的肿瘤促进因子。
Pan-cancer analysis identifies PD-L2 as a tumor promotor in the tumor microenvironment.
机构信息
Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
出版信息
Front Immunol. 2023 Mar 16;14:1093716. doi: 10.3389/fimmu.2023.1093716. eCollection 2023.
BACKGROUND
Programmed cell death protein 1 (PD-1) receptor has two ligands,programmed death-ligand 1 (PD-L1) and PD-L2. When compared with PD-L1, PD-L2 has not received much attention, and its role remains unclear.
METHODS
The expression profiles of (PD-L2-encoding gene) mRNA and PD-L2 protein were analyzed using TCGA, ICGC, and HPA databases. Kaplan-Meier and Cox regression analyses were used to assess the prognostic significance of PD-L2. We used GSEA, Spearman's correlation analysis and PPI network to explore the biological functions of PD-L2. PD-L2-associated immune cell infiltration was evaluated using the ESTIMATE algorithm and TIMER 2.0. The expressions of PD-L2 in tumor-associated macrophages (TAMs) in human colon cancer samples, and in mice in an immunocompetent syngeneic setting were verified using scRNA-seq datasets, multiplex immunofluorescence staining, and flow cytometry. After fluorescence-activated cell sorting, flow cytometry and qRT-PCR and transwell and colony formation assays were used to evaluate the phenotype and functions of PD-L2TAMs. Immune checkpoint inhibitors (ICIs) therapy prediction analysis was performed using TIDE and TISMO. Last, a series of targeted small-molecule drugs with promising therapeutic effects were predicted using the GSCA platform.
RESULTS
PD-L2 was expressed in all the common human cancer types and deteriorated outcomes in multiple cancers. PPI network and Spearman's correlation analysis revealed that PD-L2 was closely associated with many immune molecules. Moreover, both GSEA results of KEGG pathways and GSEA results for Reactome analysis indicated that PD-L2 expression played an important role in cancer immune response. Further analysis showed that expression was strongly associated with the infiltration of immune cells in tumor tissue in almost all cancer types, among which macrophages were the most positively associated with PD-L2 in colon cancer. According to the results mentioned above, we verified the expression of PD-L2 in TAMs in colon cancer and found that PD-L2TAMs population was not static. Additionally, PD-L2TAMs exhibited protumor M2 phenotype and increased the migration, invasion, and proliferative capacity of colon cancer cells. Furthermore, PD-L2 had a substantial predictive value for ICIs therapy cohorts.
CONCLUSION
PD-L2 in the TME, especially expressed on TAMs, could be applied as a potential therapeutic target.
背景
程序性死亡蛋白 1（PD-1）受体有两个配体，程序性死亡配体 1（PD-L1）和 PD-L2。与 PD-L1 相比，PD-L2 并没有受到太多关注，其作用尚不清楚。
方法
使用 TCGA、ICGC 和 HPA 数据库分析 PD-L2（编码基因）mRNA 和 PD-L2 蛋白的表达谱。使用 Kaplan-Meier 和 Cox 回归分析评估 PD-L2 的预后意义。我们使用 GSEA、Spearman 相关性分析和 PPI 网络来探讨 PD-L2 的生物学功能。使用 ESTIMATE 算法和 TIMER 2.0 评估 PD-L2 相关免疫细胞浸润。使用 scRNA-seq 数据集、多重免疫荧光染色和流式细胞术验证 PD-L2 在人结肠癌样本中的肿瘤相关巨噬细胞（TAMs）中的表达，并在免疫活性同基因小鼠模型中验证。使用荧光激活细胞分选、流式细胞术、qRT-PCR 和 Transwell 及集落形成实验评估 PD-L2TAMs 的表型和功能。使用 TIDE 和 TISMO 进行免疫检查点抑制剂（ICI）治疗预测分析。最后，使用 GSCA 平台预测一系列具有潜在治疗效果的靶向小分子药物。
结果
PD-L2 在所有常见的人类癌症类型中均有表达，并在多种癌症中导致不良预后。PPI 网络和 Spearman 相关性分析表明，PD-L2 与许多免疫分子密切相关。此外，KEGG 通路的 GSEA 结果和 Reactome 分析的 GSEA 结果均表明，PD-L2 表达在癌症免疫反应中发挥着重要作用。进一步分析表明，在几乎所有癌症类型中，表达与肿瘤组织中免疫细胞的浸润均呈强烈正相关，其中结肠癌中与 PD-L2 相关性最强的是巨噬细胞。根据上述结果，我们验证了 PD-L2 在结肠癌 TAMs 中的表达，发现 PD-L2TAMs 群体不是静态的。此外，PD-L2TAMs 表现出促肿瘤 M2 表型，并增加了结肠癌细胞的迁移、侵袭和增殖能力。此外，PD-L2 对 ICIs 治疗队列具有显著的预测价值。
结论
TME 中的 PD-L2，特别是表达在 TAMs 上的 PD-L2，可作为潜在的治疗靶点。
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