Single-cell analysis can define distinct evolution of tumor sites in follicular lymphoma
Single-cell analysis can define distinct evolution of tumor sites in follicular lymphoma
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DOI：
10.1182/blood.2020009855
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发表时间：
2021-05-27
期刊：
影响因子：
20.3
通讯作者：
Levy, Ronald
中科院分区：
文献类型：
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作者：
Haebe, Sarah;Shree, Tanaya;Levy, Ronald
肿瘤异质性使生物标志物的开发变得复杂，并促进实体恶性肿瘤的耐药性。在淋巴瘤中，我们对位点间异质性及其临床意义的了解仍然有限。在这里，我们使用单细胞 RNA、B 细胞受体 (BCR) 和 T 细胞受体测序以及流式细胞术对 10 名滤泡性淋巴瘤 (FL) 患者同步采集的 2 个淋巴结肿瘤样本进行了分析。通过跟踪快速突变的肿瘤免疫球蛋白基因，我们发现一些患者的两个肿瘤部位之间共享 BCR 亚克隆，但在许多患者中，疾病是单独发展的，肿瘤细胞在部位之间的迁移有限。表现出不同 BCR 进化的患者也表现出不同的肿瘤基因表达和细胞表面蛋白谱。虽然肿瘤微环境的总体组成在位点之间没有显着差异，但我们确实检测到位点间肿瘤异质性和滤泡辅助 T (Tfh) 细胞丰度之间的特定相关性。我们进一步观察到肿瘤和Tfh细胞之间特定配体-受体对的富集，包括CD40和CD40LG，以及肿瘤CD40表达和Tfh增殖之间的显着相关性。我们的研究可以解释对全身治疗的不一致反应，强调通过单次活检捕获患者疾病的难度，并进一步加深我们对 FL 肿瘤免疫网络的理解。
Tumor heterogeneity complicates biomarker development and fosters drug resistance in solid malignancies. In lymphoma, our knowledge of site-to-site heterogeneity and its clinical implications is still limited. Here, we profiled 2 nodal, synchronously acquired tumor samples from 10 patients with follicular lymphoma (FL) using single-cell RNA, B-cell receptor (BCR) and T-cell receptor sequencing, and flow cytometry. By following the rapidly mutating tumor immunoglobulin genes, we discovered that BCR subclones were shared between the 2 tumor sites in some patients, but in many patients, the disease had evolved separately with limited tumor cell migration between the sites. Patients exhibiting divergent BCR evolution also exhibited divergent tumor gene-expression and cell-surface protein profiles. While the overall composition of the tumor microenvironment did not differ significantly between sites, we did detect a specific correlation between site-to-site tumor heterogeneity and T follicular helper (Tfh) cell abundance. We further observed enrichment of particular ligand-receptor pairs between tumor and Tfh cells, including CD40 and CD40LG, and a significant correlation between tumor CD40 expression and Tfh proliferation. Our study may explain discordant responses to systemic therapies, underscores the difficulty of capturing a patient's disease with a single biopsy, and furthers our understanding of tumor-immune networks in FL.