Tertiary lymphoid structures improve immunotherapy and survival in melanoma
Tertiary lymphoid structures improve immunotherapy and survival in melanoma
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DOI：
10.1038/s41586-019-1914-8
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发表时间：
2020-01-01
期刊：
影响因子：
64.8
通讯作者：
Jonsson, Goran
中科院分区：
文献类型：
--
作者：
Cabrita, Rita;Lauss, Martin;Jonsson, Goran
重新激活肿瘤相关T细胞的检查点阻断疗法可以诱导持久的肿瘤控制，并导致晚期癌症患者的长期生存（1）。目前用于治疗反应的预测性生物标志物包括高水平的肿瘤内免疫活性、高肿瘤突变负荷和肠道微生物群的特定特征（2，3）。虽然T细胞在抗肿瘤反应中的作用已经得到了彻底的研究，但其他免疫细胞仍然没有得到充分的探索。在这里，我们使用转移性黑色素瘤的临床样本来研究B细胞在抗肿瘤反应中的作用，发现肿瘤相关的CD 8（+）T细胞和CD 20（+）B细胞的共存与生存率的提高相关，与其他临床变量无关。CXCR 5和CXCL 13与CD 20联合的免疫荧光染色揭示了这些CD 8（+）CD 20（+）肿瘤中三级淋巴结构的形成。我们推导出了与三级淋巴结构相关的基因特征，该基因特征预测了接受免疫检查点阻断治疗的患者队列的临床结局。此外，富含B细胞的肿瘤伴随着TCF 7（+）幼稚和/或记忆T细胞水平的增加。数字空间分析数据证实了这一点，其中没有三级淋巴结构的肿瘤中的T细胞具有功能失调的分子表型。我们的研究结果表明，三级淋巴结构在黑色素瘤的免疫微环境中发挥着关键作用，通过赋予不同的T细胞表型。肿瘤相关的CD 8（+）T细胞和CD 20（+）B细胞的共存以及三级淋巴样结构的形成与转移性黑色素瘤患者队列生存率的提高有关。
Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers(1). Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota(2,3). Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8(+) T cells and CD20(+) B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8(+)CD20(+) tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7(+) naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.The co-occurrence of tumour-associated CD8(+) T cells and CD20(+) B cells, and the formation of tertiary lymphoid structures, are linked with improved survival in cohorts of patients with metastatic melanoma.