肿瘤相关三级淋巴结构中的树突状细胞提示 Th1 细胞毒性免疫微环境,并赋予浸润 CD8+ T 细胞的阳性预后价值。

Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8+ T cells.

机构信息

Authors' Affiliations: Laboratory Immune Microenvironment and Tumors, INSERM U872, Cordeliers Research Center; University Pierre et Marie Curie; University Paris Descartes, UMRS 872; Departments of Pathology and Thoracic Surgery, Hôtel Dieu Hospital, AP-HP; Department of Pathology, Institut Mutualiste Montsouris; Department of Immunology, European Georges Pompidou Hospital, AP-HP, Paris, France; and Oncology Research, MedImmune LLC, Gaithersburg, Maryland.

出版信息

Cancer Res. 2014 Feb 1;74(3):705-15. doi: 10.1158/0008-5472.CAN-13-1342. Epub 2013 Dec 23.

Abstract

Tumor-infiltrating T cells, particularly CD45RO(+)CD8(+) memory T cells, confer a positive prognostic value in human cancers. However, the mechanisms that promote a protective T-cell response in the tumor microenvironment remain unclear. In chronic inflammatory settings such as the tumor microenvironment, lymphoid neogenesis can occur to create local lymph node-like structures known as tertiary lymphoid structures (TLS). These structures can exacerbate a local immune response, such that TLS formation in tumors may help promote an efficacious immune contexture. However, the role of TLS in tumors has yet to be investigated carefully. In lung tumors, mature dendritic cells (DC) present in tumor-associated TLS can provide a specific marker of these structures. In this study, we evaluated the influence of TLS on the characteristics of the immune infiltrate in cohorts of prospective and retrospective human primary lung tumors (n = 458). We found that a high density of mature DC correlated closely to a strong infiltration of T cells that are predominantly of the effector-memory phenotype. Moreover, mature DC density correlated with expression of genes related to T-cell activation, T-helper 1 (Th1) phenotype, and cytotoxic orientation. Lastly, a high density of TLS-associated DC correlated with long-term survival, which also allowed a distinction of patients with high CD8(+) T-cell infiltration but a high risk of death. Taken together, our results show how tumors infiltrated by TLS-associated mature DC generate a specific immune contexture characterized by a strong Th1 and cytotoxic orientation that confers the lowest risk of death. Furthermore, our findings highlight the pivotal function of TLS in shaping the immune character of the tumor microenvironment, in promoting a protective immune response mediated by T cells against cancer.

摘要

肿瘤浸润性 T 细胞,尤其是 CD45RO(+)CD8(+)记忆 T 细胞,在人类癌症中具有阳性预后价值。然而,促进肿瘤微环境中保护性 T 细胞反应的机制仍不清楚。在慢性炎症环境中,如肿瘤微环境,可能会发生淋巴样新生,形成称为三级淋巴结构(TLS)的局部淋巴结样结构。这些结构可以加剧局部免疫反应,因此肿瘤中 TLS 的形成可能有助于促进有效的免疫结构。然而,TLS 在肿瘤中的作用尚未得到仔细研究。在肺肿瘤中,存在于肿瘤相关 TLS 中的成熟树突状细胞(DC)可以提供这些结构的特异性标志物。在这项研究中,我们评估了 TLS 对前瞻性和回顾性人类原发性肺肿瘤队列(n = 458)中免疫浸润特征的影响。我们发现成熟 DC 的高密度与 T 细胞的强烈浸润密切相关,这些 T 细胞主要表现为效应记忆表型。此外,成熟 DC 密度与与 T 细胞激活、辅助性 T 细胞 1(Th1)表型和细胞毒性定向相关的基因表达相关。最后,与 TLS 相关的 DC 密度高与长期生存相关,这也可以区分具有高 CD8(+)T 细胞浸润但死亡风险高的患者。总之,我们的结果表明,TLS 浸润的肿瘤如何产生一种特定的免疫结构,其特征是强烈的 Th1 和细胞毒性定向,从而赋予最低的死亡风险。此外,我们的研究结果强调了 TLS 在塑造肿瘤微环境免疫特征、促进 T 细胞介导的抗癌保护性免疫反应方面的关键作用。

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