Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution
Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution
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DOI：
10.1002/1878-0261.12741
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发表时间：
2020-07-18
影响因子：
6.6
通讯作者：
Lohinai, Zoltan
中科院分区：
文献类型：
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作者：
Dora, David;Rivard, Christopher;Lohinai, Zoltan
小细胞肺癌(SCLC)最近被分为神经内分泌(NE)高和NE低亚型，分别表现为免疫沙漠和免疫绿洲表型。在这里，我们的目的是根据免疫检查点和人小细胞肺癌组织样本中的NE亚型在蛋白质水平上表征肿瘤微环境。在这项横断面研究中，我们包括32例早期切除的、经组织学证实的小细胞肺癌患者的原发肿瘤和匹配的淋巴结(LN)转移，这些患者之前使用NE相关的关键RNA基因将其分为NE亚型。用抗CD45、CD3、CD8、MHCII、TIM3、免疫检查点脊髓灰质炎病毒受体(PVR)和吲哚胺2，3-双加氧酶(IDO)的抗体对福尔马林固定石蜡包埋的TMA进行免疫组织化学(IHC)检测。与肿瘤巢相比，原发肿瘤和LN转移瘤中免疫细胞对间质的浸润率明显更高。NE低表达组与NE高表达组相比，瘤巢中CD45(+)细胞密度显著升高(P=0.019)，CD_8(+)效应T细胞浸润增多(P=0.003)。IDO在间质细胞和血管内皮细胞均有表达，且与原发肿瘤和LN转移瘤中较高的免疫细胞密度呈正相关，与NE类型无关。在NE低的原发肿瘤中，IDO和PVR的表达显著高于NE高的原发肿瘤(P<；0.05)。我们还发现在NE-低(与NE-高，P=0.004)的肿瘤中，恶性细胞MHC II的表达显著增加。TIM3在NE-Low(与NE-High相比，P<；0.05)和LN转移(与原发肿瘤相比，P<；0.05)中的表达显著增加。据我们所知，这是第一项人类研究表明，与去甲肾上腺素水平高的肿瘤相比，去甲肾上腺素水平低的小细胞肺癌与免疫细胞浸润增加有关。PVR、IDO、MHCII和TIM3是小细胞肺癌中新出现的检查点，在NE-Low亚型中表达增加，为进一步研究SCLC免疫治疗的潜在生物标志物和靶点提供了关键的见解。
Small cell lung cancer (SCLC) has recently been subcategorized into neuroendocrine (NE)-high and NE-low subtypes showing 'immune desert' and 'immune oasis' phenotypes, respectively. Here, we aimed to characterize the tumor microenvironment according to immune checkpoints and NE subtypes in human SCLC tissue samples at the protein level. In this cross-sectional study, we included 32 primary tumors and matched lymph node (LN) metastases of resected early-stage, histologically confirmed SCLC patients, which were previously clustered into NE subtypes using NE-associated key RNA genes. Immunohistochemistry (IHC) was performed on formalin-fixed paraffin-embedded TMAs with antibodies against CD45, CD3, CD8, MHCII, TIM3, immune checkpoint poliovirus receptor (PVR), and indoleamine 2,3-dioxygenase (IDO). The stroma was significantly more infiltrated by immune cells both in primary tumors and in LN metastases compared to tumor nests. Immune cell (CD45(+)cell) density was significantly higher in tumor nests (P = 0.019), with increased CD8(+)effector T-cell infiltration (P = 0.003) in NE-low vs NE-high tumors. The expression of IDO was confirmed on stromal and endothelial cells and was positively correlated with higher immune cell density both in primary tumors and in LN metastases, regardless of the NE pattern. Expression of IDO and PVR in tumor nests was significantly higher in NE-low primary tumors (vs NE-high,P < 0.05). We also found significantly higher MHC II expression by malignant cells in NE-low (vs NE-high,P = 0.004) tumors. TIM3 expression was significantly increased in NE-low (vs NE-high,P < 0.05) tumors and in LN metastases (vs primary tumors,P < 0.05). To our knowledge, this is the first human study that demonstratesin situthat NE-low SCLCs are associated with increased immune cell infiltration compared to NE-high tumors. PVR, IDO, MHCII, and TIM3 are emerging checkpoints in SCLC, with increased expression in the NE-low subtype, providing key insight for further prospective studies on potential biomarkers and targets for SCLC immunotherapies.