PO.TB10.07 · 肿瘤生物学
ERBB2表达与免疫格局塑造肿瘤微环境并影响食管腺癌脑转移的预后
ERBB2 expression and the immune landscape shape the tumor microenvironment and influence prognosis in esophageal adenocarcinoma brain metastases
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摘要 Abstract
中文摘要
食管腺癌（EAC）是一种常见且致命的恶性肿瘤，在全球癌症相关死亡中位居第六。EAC的脑转移罕见，仅发生于2-6%的病例，对于支撑这种转移扩散的分子驱动因素或肿瘤微环境（TME）特征所知甚少。为研究脑转移的驱动因素，我们分析了一个由冷冻原发灶与脑转移灶配对组成的测试队列（n = 8）以及一个由MD Anderson癌症中心手术（2010-2018年）所得的60例FFPE脑转移灶组成的扩展队列。为表征EAC脑转移的分子决定因素，我们进行了多组学分析，整合了全基因组测序、荧光原位杂交（FISH）和单细胞空间转录组学（10x Genomics Xenium）。ERBB2扩增作为一种反复出现且可能可靶向的改变而凸显，存在于90%的脑转移灶中，而在原发和颅外肿瘤中为20-25%，提示这是一个早期且频发的驱动事件。该队列包括12名长期生存者（LTS；>3年），其中一名患者在诊断后存活17年，而大多数患者在一年内死亡。数名患者接受了HER2靶向治疗，临床反应各异，凸显了阐明区分LTS与短期生存者（STS；<1年）因素的必要性。单细胞空间转录组学揭示了与ERBB2拷贝数相关的不同肿瘤-免疫生态系统。ERBB2高扩增的LTS肿瘤表现出免疫活跃的微环境，富含巨噬细胞、T细胞和内皮细胞，循环肿瘤细胞较少，提示有效的免疫监视。相比之下，低ERBB2肿瘤呈增殖性且免疫贫乏。在所有病例中，ERBB2表达与T细胞浸润和三级淋巴结构（TLS）相关。差异基因表达证实LTS肿瘤上调免疫激活和T细胞持久性基因（IGH1、IGH3、IGH4、IL2RB、TOX），而STS肿瘤表达促肿瘤、炎症和促血管生成基因（MUC5AC、REG4、CXCL1、CXCL3、RGS5、ACE2）。这些发现表明，ERBB2扩增和免疫背景共同塑造EAC脑转移的肿瘤微环境和预后，提示ERBB2导向治疗联合增强免疫活性的策略可能改善该患者群体的结局。
查看英文原文 English abstract
Esophageal adenocarcinoma (EAC) is a prevalent and fatal malignancy, ranking sixth globally in cancer‑related deaths. Brain metastases from EAC are rare, occurring in only 2-6% of cases, and little is known about the molecular drivers or tumor microenvironment (TME) characteristics that underpin this metastatic spread. To investigate drivers of brain metastasis, we analyzed a test cohort of frozen primary and brain metastasis pairs (n = 8) and an expansion cohort of 60 FFPE brain metastases from surgeries performed at MD Anderson Cancer Center (2010-2018).To characterize molecular determinants of EAC brain metastases, we performed multi‑omics profiling, integrating whole‑genome sequencing, fluorescence in situ hybridization (FISH), and single‑cell spatial transcriptomics (10x Genomics Xenium). ERBB2 amplification emerged as a recurrent and potentially targetable alteration, present in 90% of brain metastases versus 20-25% of primary and extracranial tumors, suggesting an early and frequent driver event. The cohort included 12 long‑term survivors (LTS; >3 years), including one patient alive 17 years post‑diagnosis, whereas most patients succumbed within one year. Several received HER2-targeted therapy with variable clinical responses, underscoring the need to elucidate factors distinguishing LTS from short-term survivors (STS; <1 year). Single‑cell spatial transcriptomics revealed distinct tumor-immune ecosystems associated with ERBB2 copy number. LTS tumors with high ERBB2 amplification exhibited immune‑active microenvironments enriched in macrophages, T cells, and endothelial cells, with fewer cycling tumor cells, indicative of effective immune surveillance. In contrast, low‑ ERBB2 tumors were proliferative and immune‑poor. Across all cases, ERBB2 expression correlated with T cell infiltration and tertiary lymphoid structures (TLS). Differential gene expression confirmed LTS tumors up-regulated immune activation and T cell persistence genes ( IGH1, IGH3, IGH4, IL2RB, TOX ), whereas STS tumors expressed pro‑tumor, inflammatory, and angiogenic genes ( MUC5AC, REG4, CXCL1, CXCL3, RGS5, ACE2 ). These findings indicate that ERBB2 amplification and immune contexture jointly shape the tumor microenvironment and prognosis in EAC brain metastases, suggesting that ERBB2 ‑directed therapies combined with strategies to enhance immune activity may improve outcomes in this patient population.
利益披露 Disclosure
N. M. Lawson, None..
I. Martín-Barrio, None..
L. Ye, None..
B. Zhao, None..
T. Mitchell, None..
M. Unal, None..
C. Cho, None..
A. Futreal, None..
K. C. Akdemir, None.