Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, 40402, Taiwan.
Translation Research Core, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan.
Sci Rep. 2020 Dec 18;10(1):22330. doi: 10.1038/s41598-020-79419-3.
Colorectal cancer (CRC) is the leading cause of cancer-related mortality worldwide. Although the role of tumor programmed cell death 1 ligand 1 (PD-L1) in suppressing antitumor immunity has been validated in various malignances, the impact of PD-L2 (PD-L2/PDCD1LG2) within tumors remains elusive. Here, we examined tumor PD-L2 expression by immunohistochemical analysis and assessed its association with clinicopathological characteristics and the infiltration of intratumoral T lymphocytes in colon carcinoma patients (n = 1264). We found that tumor PD-L2 status was correlated with perineural invasion (PNI) and associated with survival outcome in colon carcinoma patients. The level of tumor PD-L2 was positively associated with tumor PD-L1 expression but inversely associated with the density of CD8 tumor-infiltrating lymphocytes (TILs). Patients with elevated tumor PD-L2 levels had a favorable 5-year overall survival (OS) compared to patients with low PD-L2 levels (57% vs 40%, p < 0.001), especially in advanced stage colon carcinoma patients. Low tumor PD-L2 expression was associated with an increased 5-year OS risk among advanced stage colon carcinoma patients by univariate analysis [hazard ratio (HR) = 1.69, 95% CI 1.324-2.161, p < 0.001] and multivariate analysis [HR = 1.594, 95% CI 1.206-2.106, p = 0.001]. Moreover, tumor PD-L2 expression was inversely associated with the lymphocytic reaction in advanced stage colon carcinoma, suggesting that PD-L2 may be upregulated by a compensatory mechanism to inhibit T cell-mediated anticancer immunity. Taken together, these results show that tumor PD-L2 expression may be an independent prognostic factor for survival outcome in patients with advanced stage colon carcinoma.
结直肠癌（CRC）是全球癌症相关死亡的主要原因。虽然肿瘤程序性细胞死亡 1 配体 1（PD-L1）在抑制抗肿瘤免疫中的作用已在各种恶性肿瘤中得到验证，但肿瘤内 PD-L2（PD-L2/PDCD1LG2）的作用仍不清楚。在这里，我们通过免疫组织化学分析检查了肿瘤 PD-L2 的表达，并评估了其与临床病理特征和肿瘤内浸润性 T 淋巴细胞的关系在结肠癌患者（n=1264）中。我们发现肿瘤 PD-L2 状态与神经周围侵犯（PNI）相关，并与结肠癌患者的生存结果相关。肿瘤 PD-L2 水平与肿瘤 PD-L1 表达呈正相关，与 CD8 肿瘤浸润淋巴细胞（TIL）密度呈负相关。与低 PD-L2 水平的患者相比，高肿瘤 PD-L2 水平的患者具有更好的 5 年总生存率（OS）（57% vs 40%，p<0.001），尤其是晚期结肠癌患者。单因素分析显示，低肿瘤 PD-L2 表达与晚期结肠癌患者 5 年 OS 风险增加相关[风险比（HR）=1.69，95%置信区间 1.324-2.161，p<0.001]，多因素分析[HR=1.594，95%置信区间 1.206-2.106，p=0.001]。此外，肿瘤 PD-L2 表达与晚期结肠癌的淋巴细胞反应呈负相关，表明 PD-L2 可能通过代偿机制上调，以抑制 T 细胞介导的抗癌免疫。总之，这些结果表明肿瘤 PD-L2 表达可能是晚期结肠癌患者生存结果的独立预后因素。
