PD-L1 and IDO1 are potential targets for treatment in patients with primary diffuse large B-cell lymphoma of the CNS

Programmed cell death 1 (PD-1) and its ligands PD-L1 and PD-L2, as well as Indoleamine 2,3-deoxygenase (IDO1) can be expressed both by tumor and microenvironmental cells and are crucial for tumor immune escape. We aimed to evaluate the role of PD-1, its ligands and IDO1 in a cohort of patients with primary diffuse large B-cell lymphoma of the CNS (PCNSL). Tissue microarrays (TMAs) were constructed in 45 PCNSL cases. RNA extraction from whole tissue sections and RNA sequencing were successfully performed in 33 cases. Immunohistochemical stainings for PD-1, PD-L1/paired box protein 5 (PAX-5), PD-L2/PAX-5 and IDO1, and Epstein-Barr virus encoding RNA (EBER) <i>in situ</i> hybridization were analyzed. High proportions of PD-L1 and PD-L2 positive tumor cells were observed in 11% and 9% of cases, respectively. High proportions of PD-L1 and PD-L2 positive leukocytes were observed in 55% and 51% of cases, respectively. RNA sequencing revealed that gene expression of <i>IDO1</i> was high in patients with high proportion of PD-L1 positive leukocytes (<i>p</i> = .01). Protein expression of IDO1 in leukocytes was detected in 14/45 cases, in 79% of these cases a high proportion of PD-L1 positive leukocytes was observed. Gene expression of <i>IDO1</i> was high in EBER-positive cases (<i>p</i> = .0009) and protein expression of IDO1 was detected in five of six EBER-positive cases. Our study shows a significant association between gene and protein expression of IDO1 and protein expression of PD-L1 in the tumor microenvironment of PCNSL, possibly of importance for prediction of response to immunotherapies.

程序性死亡受体1（PD-1）及其配体PD-L1、PD-L2，以及吲哚胺2,3-双加氧酶1（IDO1）均可由肿瘤细胞及微环境细胞表达，在肿瘤免疫逃逸过程中发挥关键作用。本研究旨在探讨PD-1、其配体及IDO1在中枢神经系统原发性弥漫大B细胞淋巴瘤（PCNSL）患者队列中的作用。我们为45例PCNSL患者构建了组织微阵列（TMAs）。对33例患者的完整组织切片完成了RNA提取，并顺利开展RNA测序。对PD-1、PD-L1与配对盒蛋白5（PAX-5）、PD-L2与PAX-5以及IDO1进行免疫组化染色，并对EB病毒编码RNA（EBER）实施原位杂交（in situ hybridization）检测分析。结果显示，11%的病例中可见高比例PD-L1阳性肿瘤细胞，9%的病例中可见高比例PD-L2阳性肿瘤细胞；55%的病例中可见高比例PD-L1阳性白细胞，51%的病例中可见高比例PD-L2阳性白细胞。RNA测序结果表明，在PD-L1阳性白细胞比例较高的患者中，IDO1的基因表达水平显著升高（p = 0.01）。本研究在45例病例中的14例检测到白细胞IDO1的蛋白表达，其中79%的病例同时存在高比例的PD-L1阳性白细胞。EBER阳性病例的IDO1基因表达水平显著升高（p = 0.0009），且6例EBER阳性病例中有5例检测到IDO1的蛋白表达。本研究证实，PCNSL肿瘤微环境中IDO1的基因与蛋白表达，以及PD-L1的蛋白表达之间存在显著相关性，这或可为免疫治疗响应预测提供重要参考依据。