Department of Radiation Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
Acta Neuropathol Commun. 2024 Nov 26;12(1):181. doi: 10.1186/s40478-024-01895-9.
Previous studies have reported that the tumor immune microenvironment (TIME) was associated with the prognosis of lung cancer patients and the efficacy of immunotherapy. However, given the significant challenges in obtaining specimens of brain metastases (BrMs), few studies explored the correlation between the TIME and the prognosis in patients with BrMs from lung adenocarcinoma (LUAD).
Transcript profiling of archival formalin-fixed and paraffin-embedded specimens of BrMs from 70 LUAD patients with surgically resected BrMs was carried out using RNA sequencing. An immune scoring system, the green-yellow module score (GYMS), was developed to predict prognosis and immune characteristics in both BrMs and primary LUAD using Weighted Correlation Network analysis (WGCNA) and GSVA analysis. We comprehensively evaluated the immunological role of GYMS based on gene expression profile of LUAD BrMs by systematically correlating GYMS with immunological characteristics and immunotherapy responsiveness in the BrMs. Immunohistochemistry was applied for validation.
We found that the high-GYMS group had better clinical prognosis and inflamed immune landscape including high infiltrations of various immune cells, increased immunomodulatory expression, and enriched immune-related pathways by using RNA-seq and immunohistochemical analysis. Low-GYMS group presented a lacked immune infiltration characteristic. Besides, the high-GYMS group had lower TIDE score and higher T-cell inflamed score than low-GYMS group. The GYMS has been validated in independent BrMs cohorts and primary NSCLC cohort treated with anti-PD-1/PD-L1, showing strong reproducibility and stability in both primary LUAD and BrMs. In addition, we construct a GYMS-related risk signature for patients with LUAD BrMs to predict prognosis.
We identified two immune-related subtypes which used to estimate prognosis and immune characteristics and developed a reliable GYMS-related risk signature in LUAD BrMs. These results will enhance the understanding of the immune microenvironment in LUAD BrMs and lay the theoretical foundation for the development of personalized therapies for LUAD patients with BrMs.
先前的研究报告称，肿瘤免疫微环境（TIME）与肺癌患者的预后和免疫治疗的疗效有关。然而，由于获取脑转移瘤（BrMs）标本存在重大挑战，因此很少有研究探讨肺腺癌（LUAD）患者的 BrMs 中 TIME 与预后之间的相关性。
对 70 例接受手术切除 BrMs 的 LUAD 患者的 BrMs 存档福尔马林固定和石蜡包埋标本进行 RNA 测序的转录谱分析。使用加权相关网络分析（WGCNA）和 GSVA 分析，开发了一种免疫评分系统，即绿色-黄色模块评分（GYMS），以预测 BrMs 和原发性 LUAD 的预后和免疫特征。我们通过系统地将 GYMS 与 BrMs 中的免疫特征和免疫治疗反应性相关联，基于 LUAD BrMs 的基因表达谱综合评估 GYMS 的免疫作用。应用免疫组织化学进行验证。
我们发现，通过 RNA-seq 和免疫组织化学分析，高-GYMS 组具有更好的临床预后和炎症免疫景观，包括各种免疫细胞的高浸润、免疫调节表达的增加和丰富的免疫相关途径。低-GYMS 组表现出缺乏免疫浸润特征。此外，高-GYMS 组的 TIDE 评分较低，T 细胞炎症评分较高。GYMS 在独立的 BrMs 队列和接受抗 PD-1/PD-L1 治疗的原发性 NSCLC 队列中得到验证，在原发性 LUAD 和 BrMs 中均具有很强的重现性和稳定性。此外，我们构建了 LUAD BrMs 患者的 GYMS 相关风险特征，以预测预后。
我们确定了两种免疫相关亚型，用于估计预后和免疫特征，并在 LUAD BrMs 中开发了一种可靠的 GYMS 相关风险特征。这些结果将增强对 LUAD BrMs 免疫微环境的理解，并为 LUAD 伴 BrMs 患者的个性化治疗奠定理论基础。
