Presence of B Cells in Tertiary Lymphoid Structures Is Associated with a Protective Immunity in Patients with Lung Cancer
Presence of B Cells in Tertiary Lymphoid Structures Is Associated with a Protective Immunity in Patients with Lung Cancer
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DOI：
10.1164/rccm.201309-1611oc
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发表时间：
2014-04-01
影响因子：
24.7
通讯作者：
Dieu-Nosjean, Marie-Caroline
中科院分区：
文献类型：
--
作者：
Germain, Claire;Gnjatic, Sacha;Dieu-Nosjean, Marie-Caroline
原理：现在已经确定免疫反应可以发生在原发性和继发性淋巴器官之外。我们之前描述了非小细胞肺癌（NSCLC）患者中三级淋巴样结构（TLS）的存在，其特征是成熟树突状细胞（DCs）和T细胞被b细胞滤泡包围。我们证明这些成熟树突细胞的密度与良好的临床结果相关。目的：研究滤泡B细胞在非小细胞肺癌患者TLS中的作用及其与局部体液免疫反应的潜在联系。方法：采用免疫组化方法研究TLS的细胞组成。采用流式细胞术对b细胞亚群进行表征。回顾性研究在两个独立的患者队列中进行。ELISA法检测抗体特异性。测量和主要结果：与TLS组织一致，在大多数肿瘤中可检测到所有阶段的b细胞分化。生发中心体细胞超突变和类开关重组机制被激活，与浆细胞的产生有关。大约一半的患者对33种肿瘤抗原中的7种表现出抗体反应性。无论是早期NSCLC患者还是接受化疗的晚期NSCLC患者，高滤泡B细胞密度与长期生存率相关。结合卵泡B细胞和成熟DC密度，可以确定具有最佳临床结果的患者。结论：B细胞密度代表了NSCLC患者生存的一种新的预后生物标志物，并将TLS与保护性B细胞介导的免疫联系起来。
Rationale: It is now well established that immune responses can take place outside of primary and secondary lymphoid organs. We previously described the presence of tertiary lymphoid structures (TLS) in patients with non-small cell lung cancer (NSCLC) characterized by clusters of mature dendritic cells (DCs) and T cells surrounded by B-cell follicles. We demonstrated that the density of these mature DCs was associated with favorable clinical outcome.Objectives: To study the role of follicular B cells in TLS and the potential link with a local humoral immune response in patients with NSCLC.Methods: The cellular composition of TLS was investigated by immunohistochemistry. Characterization of B-cell subsets was performed by flow cytometry. A retrospective study was conducted in two independent cohorts of patients. Antibody specificity was analyzed by ELISA.Measurements and Main Results: Consistent with TLS organization, all stages of B-cell differentiation were detectable in most tumors. Germinal center somatic hypermutation and class switch recombination machineries were activated, associated with the generation of plasma cells. Approximately half of the patients showed antibody reactivity against up to 7 out of the 33 tumor antigens tested. A high density of follicular B cells correlated with long-term survival, both in patients with early-stage NSCLC and with advanced-stage NSCLC treated with chemotherapy. The combination of follicular B cell and mature DC densities allowed the identification of patients with the best clinical outcome.Conclusions: B-cell density represents a new prognostic biomarker for NSCLC patient survival, and makes the link between TLS and a protective B cell-mediated immunity.