原发乳腺癌与脑转移瘤免疫微环境特征分析揭示与 ARG2 表达相关的 T 细胞反应缺失

英文原题：Characterisation of the immune microenvironment of primary breast cancer and brain metastasis reveals depleted T-cell response associated to ARG2 expression.

PubMed 2022/11/21（内容时间） ESMO Open Q1 · IF 10.6（JCR 2025）

脑转移瘤乳腺癌地区：欧洲

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研究概要

本研究强调了原发性BC与BCBM之间的免疫学差异，以及ARG2表达在T细胞耗竭和临床结局中的潜在重要性。

研究思路结论见上方概要

背景

免疫检查点抑制是程序性死亡配体1（PD-L1）阳性转移性三阴性（TN）乳腺癌（BC）的既定治疗方法。然而，乳腺癌脑转移（BCBM）的免疫景观仍不明确。

方法

在原发性BC和BCBM中，评估了TIL（肿瘤浸润淋巴细胞）（TILs）以及770个免疫相关基因的messenger RNA（mRNA）水平（NanoString，nCounter Immuno-oncology IO360）。确定了ARG2转录本和蛋白表达在原发性BC中的预后作用及其与结局的关联。

结果

与原发性BC相比，BCBM中TILs显著减少。11.5%的BC呈现高免疫浸润（热），46.2%为改变型（免疫抑制/排除），34.6%为冷型（无/低免疫浸润）。3.8%的BCBM为热型，23.1%为改变型，73.1%为冷型。与原发性BC相比，BCBM中有112个免疫相关基因（包括PD-L1和CTLA4）表达降低（错误发现率<0.01，log2倍数变化>1.5）。这些基因涉及基质重塑和转移、细胞因子-趋化因子信号传导、淋巴区室、抗原呈递以及免疫细胞黏附和迁移。免疫调节因子如PD-L1（CD274）、CTLA4、TIGIT和CD276（B7H3）在BCBM中降低。然而，与雌激素受体阳性BCBM相比，TN BCBM中PD-L1和CTLA4表达显著更高（P = 0.01），CTLA4表达在人表皮生长因子受体2阳性中也高（P < 0.01）。ARG2是BCBM中上调的四个基因之一。原发性BC中高ARG2 mRNA表达与更差的远处无转移生存相关（P = 0.038），而ARG2蛋白表达与更差的乳腺-脑无转移生存（P = 0.027）和总生存（P = 0.019）相关。ARG2高转录水平与BC和BCBM中低水平的细胞毒性和T细胞相关（P < 0.01）。

展开英文摘要原文

BACKGROUND: Immune checkpoint inhibition is an established treatment in programmed death-ligand 1 (PD-L1)-positive metastatic triple-negative (TN) breast cancer (BC). However, the immune landscape of breast cancer brain metastasis (BCBM) remains poorly defined. MATERIALS AND METHODS: The tumour-infiltrating lymphocytes (TILs) and the messenger RNA (mRNA) levels of 770 immune-related genes (NanoString , nCounter Immuno-oncology IO360) were assessed in primary BCs and BCBMs. The prognostic role of ARG2 transcripts and protein expression in primary BCs and its association with outcome was determined. RESULTS: There was a significant reduction of TILs in the BCBMs in comparison to primary BCs. 11.5% of BCs presented a high immune infiltrate (hot), 46.2% were altered (immunosuppressed/excluded) and 34.6% were cold (no/low immune infiltrate). 3.8% of BCBMs were hot, 23.1% altered and 73.1% cold. One hundred and twelve immune-related genes including PD-L1 and CTLA4 were decreased in BCBM compared to the primary BCs (false discovery rate <0.01, log2 fold-change >1.5). These genes are involved in matrix remodelling and metastasis, cytokine-chemokine signalling, lymphoid compartment, antigen presentation and immune cell adhesion and migration. Immuno-modulators such as PD-L1 (CD274), CTLA4, TIGIT and CD276 (B7H3) were decreased in BCBMs. However, PD-L1 and CTLA4 expression was significantly higher in TN BCBMs (P = 0.01), with CTLA4 expression also high in human epidermal growth factor receptor 2-positive (P < 0.01) compared to estrogen receptor-positive BCBMs. ARG2 was one of four genes up-regulated in BCBMs. High ARG2 mRNA expression in primary BCs was associated with worse distant metastasis-free survival (P = 0.038), while ARG2 protein expression was associated with worse breast-brain metastasis-free (P = 0.027) and overall survival (P = 0.019). High transcript levels of ARG2 correlated to low levels of cytotoxic and T cells in both BC and BCBM (P < 0.01). CONCLUSION: This study highlights the immunological differences between primary BCs and BCBMs and the potential importance of ARG2 expression in T-cell depletion and clinical outcome.

论文信息

作者: Giannoudis A、Varešlija D、Sharma V、Zakaria R、Platt-Higgins A、Rudland PS、Jenkinson MD、Young LS
第一作者单位: Institute of Systems, Molecular and Integrative Biology, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.United Kingdom
通讯作者单位: Institute of Systems, Molecular and Integrative Biology, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK; The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK. Electronic address: c.palmieri@liverpool.ac.uk.United Kingdom
文献类型: 非美国政府资助研究
期刊: ESMO open2022 Dec

原文标识: PubMed 36423363　·　DOI 10.1016/j.esmoop.2022.100636

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