PD-L1 and PD-L2 expression in the tumor microenvironment including peritumoral tissue in primary central nervous system lymphoma
PD-L1 and PD-L2 expression in the tumor microenvironment including peritumoral tissue in primary central nervous system lymphoma
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DOI：
10.1186/s12885-020-06755-y
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发表时间：
2020-04-05
期刊：
影响因子：
3.8
通讯作者：
Miyatake, Shin-Ichi
中科院分区：
文献类型：
--
作者：
Furuse, Motomasa;Kuwabara, Hiroko;Miyatake, Shin-Ichi
背景原发性中枢神经系统淋巴瘤(PCNSL)中肿瘤细胞和肿瘤浸润性免疫细胞上的程序性死亡配体1(PD-L1)和PD-L2的表达尚不清楚。在本研究中，我们分析了PCNSL患者的针吸活检和开颅标本，以比较肿瘤和瘤周组织中PD-L1和PD-L2的水平。我们还评估了生物学因素与PD-L1和PD-L2表达的预后意义之间的相关性。方法回顾分析70例经组织学确诊的弥漫性大B细胞淋巴瘤患者的临床资料。采用免疫组织化学方法检测CD20、CD68、PD-L1、PD-L2的表达。在开颅标本中，测定肿瘤和瘤周组织中PD-L1和PD-L2阳性巨噬细胞的百分比。生存分析采用Kaplan-Meier法，采用对数等级检验和Cox比例风险模型。结果肿瘤细胞很少表达PD-L1和PD-L2，而巨噬细胞表达PD-L1和PD-L2，多数患者肿瘤细胞表达PD-L1和PD-L2。PD-L2阳性细胞在瘤周巨噬细胞中的中位数百分比(32.5%；95%CI：0~94.6)显著高于瘤内巨噬细胞(27.5%；95%CI：0~81.1，p=0.0014)。PD-L2阳性的瘤内巨噬细胞与瘤周巨噬细胞的百分率呈显著正相关(P=0.0429)，相关系数很低(Rho=0.098535)。巨噬细胞上PD-L1的表达与生物学因素显著相关(瘤内巨噬细胞：较好的KPS，p=0.0008；较好的MSKCC评分，p=0.0103；瘤周巨噬细胞：低比例的乳酸脱氢酶升高，p=0.0064)和较长的OS(瘤内巨噬细胞：高PD-L1=60个月，95%CI=30-132.6；低PD-L1=24个月，95%CI=11-48；p=0.032；瘤周巨噬细胞：高PD-L1=60个月，95%CI=30.7-NR；低PD-L1=14个月，95%CI=3~26)。PD-L1在瘤周巨噬细胞的表达预示着良好的预后(HR=0.30，95%CI=0.12-0.77，P=0.0129)。结论瘤内和瘤周巨噬细胞表达PD-L1和PD-L2的比率高于肿瘤细胞。PD-L1的表达，尤其是瘤周巨噬细胞的表达，似乎是影响PCNSL预后的重要因素。未来有必要对包括瘤周组织在内的肿瘤微环境中的检查点分子进行全面分析。
Background The prevalence of programmed death-ligand 1 (PD-L1) and PD-L2 expression on tumor cells and tumor-infiltrating immune cells in primary central nervous system lymphoma (PCNSL) remains unclear. In the present study, we analyzed needle biopsy and craniotomy specimens of patients with PCNSL to compare the PD-L1 and PD-L2 levels in the tumor and surrounding (peritumoral) tissue. We also assessed the correlation between biological factors and the prognostic significance of PD-L1 and PD-L2 expression. Methods We retrospectively analyzed the cases of 70 patients histologically diagnosed with PCNSL (diffuse large B-cell lymphoma). Immunohistochemistry for CD20, CD68, PD-L1, and PD-L2 was performed. In cases with specimens taken by craniotomy, the percentages of PD-L1- and PD-L2-positive macrophages were evaluated in both tumor and peritumoral tissue. The Kaplan-Meier method with log-rank test and Cox proportional hazard model were used for survival analysis. Results The tumor cells expressed little or no PD-L1 and PD-L2, but macrophages expressed PD-L1 and PD-L2 in most of the patients. The median percentage of PD-L2-positive cells was significantly higher among peritumoral macrophages (32.5%; 95% CI: 0-94.6) than intratumoral macrophages (27.5%; 95% CI: 0-81.1, p = 0.0014). There was a significant correlation between the percentages of PD-L2-positive intratumoral macrophages and PD-L2-positive peritumoral macrophages (p = 0.0429), with very low coefficient correlation (rho = 0.098535). PD-L1 expression on macrophages was significantly associated with biological factors (intratumoral macrophages: better KPS, p = 0.0008; better MSKCC score, p = 0.0103; peritumoral macrophages: low proportion of LDH elevation, p = 0.0064) and longer OS (for intratumoral macrophages: high PD-L1 = 60 months, 95% CI = 30-132.6; low PD-L1 = 24 months, 95% CI = 11-48; p = 0.032; for peritumoral macrophages: high PD-L1 = 60 months, 95% CI = 30.7-NR; low PD-L1 = 14 months, 95% CI = 3-26). PD-L1 expression on peritumoral macrophages was strongly predictive of a favorable outcome (HR = 0.30, 95% CI = 0.12-0.77, p = 0.0129). Conclusions Macrophages in intratumoral and peritumoral tissue expressed PD-L1 and PD-L2 at a higher rate than tumor cells. PD-L1 expression, especially on peritumoral macrophages, seems to be an important prognostic factor in PCNSL. Future comprehensive analysis of checkpoint molecules in the tumor microenvironment, including the peritumoral tissue, is warranted.