Tumor lineage-specific immune response in brain metastatic disease: opportunities for targeted immunotherapy regimen?

IF 6.2 2区医学 Q1 NEUROSCIENCES

Acta Neuropathologica Communications Pub Date : 2023-04-15 DOI:10.1186/s40478-023-01542-9

Shiva Najjary, Johan M Kros, Willem de Koning, Disha Vadgama, Karishma Lila, Janina Wolf, Dana A M Mustafa

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引用次数: 1

Abstract

Metastases in the brain are the most severe and devastating complication of cancer. The incidence of brain metastasis is increasing. Therefore, the need of finding specific druggable targets for brain metastasis is demanding. The aim of this study was to compare the brain (immune) response to brain metastases of the most common tumor lineages, viz., lung adenocarcinoma and breast cancer. Targeted gene expression profiles of 11 brain metastasis of lung adenocarcinoma (BM-LUAD) were compared to 11 brain metastasis of breast cancer (BCBM) using NanoString nCounter PanCancer IO 360™ Panel. The most promising results were validated spatially using the novel GeoMx™ Digital Spatial Profiler (DSP) Technology. Additionally, Immune cell profiles and expression of drug targets were validated by multiplex immunohistochemistry. We found a more active immune response in BM-LUAD as compared to BCBM. In the BM-LUAD, 138 genes were upregulated as compared to BCBM (adj. p ≤ 0.05). Conversely, in BCBM 28 genes were upregulated (adj. p ≤ 0.05). Additionally, genes related to CD45 + cells, T cells, and cytotoxic T cells showed to be expressed higher in BM-LUAD compared to BCBM (adj. p = 0.01, adj. p = 0.023, adj. p = 0.023, respectively). The spatial quantification of the immune cells using the GeoMx DSP technique revealed the significantly higher quantification of CD14 and CD163 in tumor regions of BM-LUAD as compared to BCBM. Importantly, the immune checkpoint VISTA and IDO1 were identified as highly expressed in the BM-LUAD. Multiplex immunohistochemistry confirmed the finding and showed that VISTA is expressed mainly in BM-LUAD tumor cells, CD3 + cells, and to fewer levels in some microglial cells in BM-LUAD. This is the first report on differences in the brain immune response between metastatic tumors of different lineages. We found a far more extensive infiltration of immune cells in BM-LUAD as compared to BCBM. In addition, we found higher expression of VISTA and IDO1 in BM-LUAD. Taken together, targeted immune therapy should be considered to treat patients with BM-LUAD.

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脑转移性疾病的肿瘤谱系特异性免疫反应:靶向免疫治疗方案的机会?

脑转移是癌症最严重、最具破坏性的并发症。脑转移的发病率呈上升趋势。因此，寻找脑转移的特异性药物靶点是迫切需要的。本研究的目的是比较脑(免疫)反应对脑转移最常见的肿瘤谱系，即肺腺癌和乳腺癌。采用NanoString nCounter PanCancer IO 360™Panel对11例肺腺癌脑转移瘤(BM-LUAD)和11例乳腺癌脑转移瘤(BCBM)的靶向基因表达谱进行比较。使用新型的GeoMx™数字空间分析器(DSP)技术对最有希望的结果进行了空间验证。此外，免疫细胞谱和药物靶点的表达通过多重免疫组织化学验证。我们发现，与BCBM相比，BM-LUAD的免疫反应更为活跃。与BCBM相比，BM-LUAD中有138个基因表达上调(adj. p≤0.05)。相反，BCBM中有28个基因表达上调(adj. p≤0.05)。此外，与BCBM相比，BM-LUAD中CD45 +细胞、T细胞和细胞毒性T细胞相关基因的表达更高(相对值p = 0.01，相对值p = 0.023，相对值p = 0.023)。利用GeoMx DSP技术对免疫细胞进行空间定量，结果显示BM-LUAD肿瘤区域的CD14和CD163的定量明显高于BCBM。重要的是，免疫检查点VISTA和IDO1在BM-LUAD中被鉴定为高表达。多重免疫组化证实了这一发现，表明VISTA主要在BM-LUAD肿瘤细胞、CD3 +细胞中表达，在BM-LUAD的一些小胶质细胞中表达较少。这是关于不同谱系转移性肿瘤脑免疫反应差异的第一份报告。我们发现与BCBM相比，BM-LUAD中免疫细胞的浸润要广泛得多。此外，我们发现VISTA和IDO1在BM-LUAD中表达较高。综上所述，治疗BM-LUAD患者应考虑靶向免疫治疗。

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来源期刊

Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine

CiteScore

11.20

自引率

2.80%

发文量

162

审稿时长

8 weeks

期刊介绍： "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.