Single-cell spatial analysis of tumor immune architecture in diffuse large B-cell lymphoma.
Single-cell spatial analysis of tumor immune architecture in diffuse large B-cell lymphoma.
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DOI：
10.1182/bloodadvances.2022007493
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发表时间：
2022-08-23
期刊：
影响因子：
7.5
通讯作者：
Merchant, Akil
中科院分区：
文献类型：
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作者：
Colombo, Anthony R;Hav, Monirath;Singh, Mohan;Xu, Alexander;Gamboa, Alicia;Lemos, Tucker;Gerdtsson, Erik;Chen, Denaly;Houldsworth, Jane;Shaknovich, Rita;Aoki, Tomohiro;Chong, Lauren;Takata, Katsuyoshi;Chavez, Elizabeth A;Steidl, Christian;Hicks, James;Kuhn, Peter;Siddiqi, Imran;Merchant, Akil
我们使用IMC来证明在同源肿瘤如DLBCL中，存在逃避免疫渗透的肿瘤细胞袋。我们确定了与化疗耐药性和突变特征相关的TME特征，并确定了DLBCL的免疫学结构。癌症中肿瘤微环境（TME）的多重免疫细胞分析提高了我们对癌症免疫学的理解，但缺乏淋巴瘤中肿瘤-免疫相互作用的复杂空间分析。在这里，我们使用成像质量细胞术（IMC）对33例弥漫性大B细胞淋巴瘤（DLBCL）的肿瘤和免疫细胞结构的特点，并将其与临床病理特征，如细胞的起源，基因突变，化疗的反应。为了了解DLBCL对免疫检查点抑制剂（ICI）的不良反应，我们将我们的结果与霍奇金淋巴瘤（一种对ICI高度反应的癌症）的IMC数据进行了比较，并观察了PD-L1，PD-1和TIM-3表达的差异。我们建立了一个肿瘤细胞的空间分类，并确定了DLBCL拓扑结构内免疫激活，免疫抑制和免疫排斥的肿瘤中心亚区。最后，空间分析使我们能够识别出与免疫细胞渗透到免疫沙漠区域相关的标记物，如CXCR 3，这对工程细胞疗法具有重要意义。这是第一项将肿瘤突变谱、细胞来源分类和TME的多重免疫表型整合到单细胞水平DLBCL空间分析中的研究。我们证明，远不是组织病理学单调，DLBCL具有复杂的肿瘤结构，肿瘤拓扑结构的变化与临床相关特征相关。该分析确定了与免疫肿瘤学和细胞疗法中的联合治疗策略相关的候选生物标志物和治疗靶点，如TIM-3、CCR 4和CXCR 3。
We use IMC to demonstrate that among homogenous tumors such as DLBCL, there are pockets of tumor cells that escape immune penetration. We identify TME features that correlate with chemo-resistance and mutational signatures and identify an immunological structure in DLBCL. Multiplexed immune cell profiling of the tumor microenvironment (TME) in cancer has improved our understanding of cancer immunology, but complex spatial analyses of tumor-immune interactions in lymphoma are lacking. Here, we used imaging mass cytometry (IMC) on 33 cases of diffuse large B-cell lymphoma (DLBCL) to characterize tumor and immune cell architecture and correlate it to clinicopathological features such as cell of origin, gene mutations, and responsiveness to chemotherapy. To understand the poor response of DLBCL to immune checkpoint inhibitors (ICI), we compared our results to IMC data from Hodgkin lymphoma, a cancer highly responsive to ICI, and observed differences in the expression of PD-L1, PD-1, and TIM-3. We created a spatial classification of tumor cells and identified tumor-centric subregions of immune activation, immune suppression, and immune exclusion within the topology of DLBCL. Finally, the spatial analysis allowed us to identify markers such as CXCR3, which are associated with penetration of immune cells into immune desert regions, with important implications for engineered cellular therapies. This is the first study to integrate tumor mutational profiling, cell of origin classification, and multiplexed immuno-phenotyping of the TME into a spatial analysis of DLBCL at the single-cell level. We demonstrate that, far from being histopathologically monotonous, DLBCL has a complex tumor architecture, and that changes in tumor topology can be correlated with clinically relevant features. This analysis identifies candidate biomarkers and therapeutic targets such as TIM-3, CCR4, and CXCR3 that are relevant for combination treatment strategies in immuno-oncology and cellular therapies.