INTRODUCTION A comprehensive characterization of the tumour microenvironment is lacking in neuroendocrine tumours (NETs), where programmed cell death-1 receptor-ligand (PD-1/PD-L1) inhibitors are undergoing efficacy testing. OBJECTIVE We investigated drivers of cancer-related immunosuppression across NETs of various sites and grades using multi-parameter immunohistochemistry and targeted transcriptomic profiling. METHODS Tissue microarrays (n = 102) were stained for PD-L1 and 2 and indoleamine deoxygenase-1 (IDO-1) and evaluated in relationship to functional characteristics of tumour-infiltrating T-lymphocytes (TILs) and biomarkers of hypoxia/angiogenesis. PD-L1 expression was tested in circulating tumour cells (CTCs, n = 12) to evaluate its relationship with metastatic dissemination. RESULTS PD-L1 expression was highest in lung NETs (n = 30, p = 0.007), whereas PD-L2 was highest in pancreatic NETs (n = 53, p < 0.001) with no correlation with grade or hypoxia/angiogenesis. PD-L1+ NETs (n = 26, 25%) had greater CD4+/FOXP3+ and CD8+/PD1+ TILs (p < 0.001) and necrosis (p = 0.02). CD4+/FOXP3+ infiltrate had the highest PD-L1/IDO-1 co-expressing tumours (p = 0.006). Grade 3 well-differentiated NETs had lower CD4+/FOXP3+ and CD8+/PD1+ TIL density (p < 0.001), and NanoString immune profiling revealed enrichment of macrophage-related transcripts in cases with poorer prognosis. We identified PD-L1(+) CTC subpopulations in 75% of evaluated patients (n = 12). CONCLUSIONS PD-L1 expression correlates with T-cell exhaustion independent of tumour hypoxia and is enhanced in a subpopulation of CTCs, suggesting its relevance to the progression of NETs. These findings support a potential therapeutic role for PD-L1 inhibitors in a subset of NETs.

中文翻译：

---

程序性细胞死亡配体表达驱动神经内分泌肿瘤不同亚型的免疫耐受发生。

引言 神经内分泌肿瘤 (NET) 缺乏对肿瘤微环境的全面表征，其中程序性细胞死亡 1 受体配体 (PD-1/PD-L1) 抑制剂正在进行功效测试。目标我们使用多参数免疫组织化学和靶向转录组学分析研究了不同部位和级别的 NET 中癌症相关免疫抑制的驱动因素。方法 对组织微阵列（n = 102）进行 PD-L1 和 2 以及吲哚胺脱氧酶-1 (IDO-1) 染色，并评估与肿瘤浸润性 T 淋巴细胞 (TIL) 的功能特征和缺氧/血管生成生物标志物的关系。在循环肿瘤细胞（CTC，n = 12）中测试了 PD-L1 表达，以评估其与转移性播散的关系。结果 PD-L1 表达在肺 NET 中最高（n = 30，p = 0.007），而 PD-L2 在胰腺 NET 中最高（n = 53，p < 0.001），与分级或缺氧/血管生成无关。PD-L1+ NETs (n = 26, 25%) 有更多的 CD4+/FOXP3+ 和 CD8+/PD1+ TILs (p < 0.001) 和坏死 (p = 0.02)。CD4+/FOXP3+ 浸润具有最高的 PD-L1/IDO-1 共表达肿瘤（p = 0.006）。3 级分化良好的 NET 具有较低的 CD4+/FOXP3+ 和 CD8+/PD1+ TIL 密度（p < 0.001），并且 NanoString 免疫分析显示在预后较差的情况下巨噬细胞相关转录物富集。我们在 75% 的评估患者（n = 12）中确定了 PD-L1(+) CTC 亚群。结论 PD-L1 表达与独立于肿瘤缺氧的 T 细胞耗竭相关，并且在 CTC 亚群中增强，表明其与 NET 的进展相关。