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Abstract：
BACKGROUND: Advancements in immunotherapeutic approaches only had a modest impact on the therapy of lung neuroendocrine neoplasms (LNENs). Our multicenter study aimed to investigate the expression patterns of novel immunotherapy targets in intermediate- and high-grade LNENs.
METHODS: The expressions of V-domain Ig suppressor of T cell activation (VISTA), OX40L, Glucocorticoid-induced TNF receptor (GITR), and T cell immunoglobulin and mucin domain 3 (TIM3) proteins were measured by immunohistochemistry in surgically resected tumor samples of 26 atypical carcinoid (AC), 49 large cell neuroendocrine lung cancer (LCNEC), and 66 small cell lung cancer (SCLC) patients. Tumor and immune cells were separately scored.
RESULTS: Tumor cell TIM3 expression was the highest in ACs (p < 0.001), whereas elevated tumor cell GITR levels were characteristic for both ACs and SCLCs (p < 0.001 and p = 0.011, respectively). OX40L expression of tumor cells was considerably lower in ACs (vs. SCLCs; p < 0.001). Tumor cell VISTA expression was consistently low in LNENs, with no significant differences across histological subtypes. ACs were the least immunogenic tumors concerning immune cell abundance (p < 0.001). Immune cell VISTA and GITR expressions were also significantly lower in these intermediate-grade malignancies than in SCLCs or in LCNECs. Immune cell TIM3 and GITR expressions were associated with borderline prognostic significance in our multivariate model (p = 0.057 and p = 0.071, respectively).
CONCLUSIONS: LNEN subtypes have characteristic and widely divergent VISTA, OX40L, GITR, and TIM3 protein expressions. By shedding light on the different expression patterns of these immunotherapy targets, the current multicenter study provides support for the future implementation of novel immunotherapeutic approaches.
METHODS: The expressions of V-domain Ig suppressor of T cell activation (VISTA), OX40L, Glucocorticoid-induced TNF receptor (GITR), and T cell immunoglobulin and mucin domain 3 (TIM3) proteins were measured by immunohistochemistry in surgically resected tumor samples of 26 atypical carcinoid (AC), 49 large cell neuroendocrine lung cancer (LCNEC), and 66 small cell lung cancer (SCLC) patients. Tumor and immune cells were separately scored.
RESULTS: Tumor cell TIM3 expression was the highest in ACs (p < 0.001), whereas elevated tumor cell GITR levels were characteristic for both ACs and SCLCs (p < 0.001 and p = 0.011, respectively). OX40L expression of tumor cells was considerably lower in ACs (vs. SCLCs; p < 0.001). Tumor cell VISTA expression was consistently low in LNENs, with no significant differences across histological subtypes. ACs were the least immunogenic tumors concerning immune cell abundance (p < 0.001). Immune cell VISTA and GITR expressions were also significantly lower in these intermediate-grade malignancies than in SCLCs or in LCNECs. Immune cell TIM3 and GITR expressions were associated with borderline prognostic significance in our multivariate model (p = 0.057 and p = 0.071, respectively).
CONCLUSIONS: LNEN subtypes have characteristic and widely divergent VISTA, OX40L, GITR, and TIM3 protein expressions. By shedding light on the different expression patterns of these immunotherapy targets, the current multicenter study provides support for the future implementation of novel immunotherapeutic approaches.
摘要：
背景：免疫治疗方法的进展对肺神经内分泌肿瘤（LNENs）的治疗仅有适度的影响。我们的多中心研究旨在研究中高级LNEN中新型免疫疗法靶标的表达模式。
方法：T细胞激活的V域Ig抑制因子（VISTA）的表达，OX40L,糖皮质激素诱导的TNF受体（GITR），和T细胞免疫球蛋白和粘蛋白结构域3（TIM3）蛋白通过免疫组织化学在手术切除的26个非典型类癌（AC）的肿瘤样本中测量，49大细胞神经内分泌肺癌（LCNEC），66例小细胞肺癌（SCLC）患者。分别对肿瘤和免疫细胞进行评分。
结果：肿瘤细胞TIM3表达在ACs中最高（p<0.001），而升高的肿瘤细胞GITR水平是AC和SCLC的特征（分别为p<0.001和p=0.011）。肿瘤细胞的OX40L表达在ACs中明显较低（与SCLC；p<0.001）。LNEN中肿瘤细胞VISTA的表达一直很低，在组织学亚型之间没有显着差异。关于免疫细胞丰度,AC是免疫原性最低的肿瘤(p<0.001)。免疫细胞VISTA和GITR表达在这些中级恶性肿瘤中也显著低于SCLC或LCNEC。在我们的多变量模型中，免疫细胞TIM3和GITR表达与临界预后意义相关（分别为p=0.057和p=0.071）。
结论：LNEN亚型具有特征性和广泛分歧的VISTA，OX40L,GITR,和TIM3蛋白表达。通过揭示这些免疫治疗靶点的不同表达模式，当前的多中心研究为新的免疫治疗方法的未来实施提供了支持.
方法：T细胞激活的V域Ig抑制因子（VISTA）的表达，OX40L,糖皮质激素诱导的TNF受体（GITR），和T细胞免疫球蛋白和粘蛋白结构域3（TIM3）蛋白通过免疫组织化学在手术切除的26个非典型类癌（AC）的肿瘤样本中测量，49大细胞神经内分泌肺癌（LCNEC），66例小细胞肺癌（SCLC）患者。分别对肿瘤和免疫细胞进行评分。
结果：肿瘤细胞TIM3表达在ACs中最高（p<0.001），而升高的肿瘤细胞GITR水平是AC和SCLC的特征（分别为p<0.001和p=0.011）。肿瘤细胞的OX40L表达在ACs中明显较低（与SCLC；p<0.001）。LNEN中肿瘤细胞VISTA的表达一直很低，在组织学亚型之间没有显着差异。关于免疫细胞丰度,AC是免疫原性最低的肿瘤(p<0.001)。免疫细胞VISTA和GITR表达在这些中级恶性肿瘤中也显著低于SCLC或LCNEC。在我们的多变量模型中，免疫细胞TIM3和GITR表达与临界预后意义相关（分别为p=0.057和p=0.071）。
结论：LNEN亚型具有特征性和广泛分歧的VISTA，OX40L,GITR,和TIM3蛋白表达。通过揭示这些免疫治疗靶点的不同表达模式，当前的多中心研究为新的免疫治疗方法的未来实施提供了支持.
