Despite some success in secondary brain metastases, targeted or immune-based therapies have shown limited efficacy against primary brain malignancies such as glioblastoma (GBM). Although the intratumoral heterogeneity of GBM is implicated in treatment resistance, it remains unclear whether this diversity is observed within brain metastases and to what extent cancer cell–intrinsic heterogeneity sculpts the local immune microenvironment. Here, we profiled the immunogenomic state of 93 spatially distinct regions from 30 malignant brain tumors through whole-exome, RNA, and T-cell receptor sequencing. Our analyses identified differences between primary and secondary malignancies, with gliomas displaying more spatial heterogeneity at the genomic and neoantigen levels. In addition, this spatial diversity was recapitulated in the distribution of T-cell clones in which some gliomas harbored highly expanded but spatially restricted clonotypes. This study defines the immunogenomic landscape across a cohort of malignant brain tumors and contains implications for the design of targeted and immune-based therapies against intracranial malignancies. Significance: This study describes the impact of spatial heterogeneity on genomic and immunologic characteristics of gliomas and brain metastases. The results suggest that gliomas harbor significantly greater intratumoral heterogeneity of genomic alterations, neoantigens, and T-cell clones than brain metastases, indicating the importance of multisector analysis for clinical or translational studies. This article is highlighted in the In This Issue feature, [p. 1][1] [1]: /lookup/volpage/12/1?iss=1

中文翻译：

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通过多部门分析表征恶性脑肿瘤的基因组和免疫多样性

尽管在继发性脑转移中取得了一些成功，但靶向或基于免疫的疗法对原发性脑恶性肿瘤如胶质母细胞瘤 (GBM) 的疗效有限。尽管 GBM 的瘤内异质性与治疗抗性有关，但尚不清楚这种多样性是否在脑转移瘤中观察到，以及癌细胞-内在异质性在多大程度上塑造了局部免疫微环境。在这里，我们通过全外显子组、RNA 和 T 细胞受体测序分析了来自 30 个恶性脑肿瘤的 93 个空间不同区域的免疫基因组状态。我们的分析确定了原发性和继发性恶性肿瘤之间的差异，胶质瘤在基因组和新抗原水平上表现出更多的空间异质性。此外，这种空间多样性在 T 细胞克隆的分布中得到了概括，其中一些神经胶质瘤具有高度扩增但空间受限的克隆型。这项研究定义了一组恶性脑肿瘤的免疫基因组学格局，并对针对颅内恶性肿瘤的靶向和基于免疫的疗法的设计产生了影响。意义：本研究描述了空间异质性对胶质瘤和脑转移瘤的基因组和免疫学特征的影响。结果表明，与脑转移瘤相比，胶质瘤的基因组改变、新抗原和 T 细胞克隆的瘤内异质性显着增加，这表明多部门分析对于临床或转化研究的重要性。本文在 In This Issue 功能中突出显示，[p. 1][1] [1]：