Tumor-Infiltrating B Lymphocyte Profiling Identifies IgG-Biased, Clonally Expanded Prognostic Phenotypes in Triple-Negative Breast Cancer.
Tumor-Infiltrating B Lymphocyte Profiling Identifies IgG-Biased, Clonally Expanded Prognostic Phenotypes in Triple-Negative Breast Cancer.
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肿瘤浸润B淋巴细胞分析鉴定出三阴性乳腺癌中IgG偏向性、克隆性扩增的预后表型
DOI：
10.1158/0008-5472.can-20-3773
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发表时间：
2021-08-15
期刊：
影响因子：
11.2
通讯作者：
Karagiannis SN
中科院分区：
文献类型：
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作者：
Harris RJ;Cheung A;Ng JCF;Laddach R;Chenoweth AM;Crescioli S;Fittall M;Dominguez-Rodriguez D;Roberts J;Levi D;Liu F;Alberts E;Quist J;Santaolalla A;Pinder SE;Gillett C;Hammar N;Irshad S;Van Hemelrijck M;Dunn-Walters DK;Fraternali F;Spicer JF;Lacy KE;Tsoka S;Grigoriadis A;Tutt ANJ;Karagiannis SN
肿瘤浸润性B淋巴细胞聚集成簇，经历B细胞受体驱动的活化、增殖和同种型转换。克隆扩增的IgG同种型偏向性体液免疫与主要在三阴性乳腺癌中的良好预后相关。在乳腺癌中，体液免疫应答可能有助于临床结果，特别是在更具免疫原性的亚型中。在这里，我们研究了乳腺肿瘤中的B淋巴细胞亚群、免疫球蛋白表达和克隆特征，重点是侵袭性三阴性乳腺癌（TNBC）。在来自TNBC患者和健康志愿者的样品中，评价了循环和肿瘤浸润B淋巴细胞（TIL-B）。与匹配血液相比，肿瘤中的CD 20 + CD 27 +IgD−同种型转换的B淋巴细胞增加。TIL-B经常与T淋巴细胞形成基质簇，并参与双向功能性串扰，与淋巴组装、共刺激、嘌呤-细胞因子受体相互作用、细胞毒性T细胞活化和T细胞依赖性B细胞活化相关的基因特征一致。TIL-B上调B细胞受体（BCR）途径分子FOS和JUN、生发中心趋化因子调节因子RGS 1、活化标志物CD 69和通过NFκB的TNFα信号转导，表明BCR-免疫复合物形成。与其他亚型和正常乳腺相比，TNBC中与B淋巴细胞募集和淋巴样装配相关的基因（包括CXCL 13、CXCR 4和DC-LAMP）的表达升高。富含TIL-B的肿瘤显示IgG而不是伊加同种型的扩增，IgG同种型转换与TNBC的生存结局呈正相关。克隆扩增偏向IgG，显示具有特定可变区基因组合和狭窄谱系的广泛克隆家族。较强的阳性选择压力存在于IgG的互补决定区相比，其克隆相关的伊加在肿瘤样品。总体而言，类别转换的B淋巴细胞谱系特征在TNBC中是显著的，与改善的临床结果相关，并赋予IgG偏倚的、克隆扩增的和可能的抗原驱动的体液应答。肿瘤浸润性B淋巴细胞聚集成簇，经历B细胞受体驱动的活化、增殖和同种型转换。克隆扩增的IgG同种型偏向性体液免疫与主要在三阴性乳腺癌中的良好预后相关。
Tumor-infiltrating B lymphocytes assemble in clusters, undergoing B-cell receptor–driven activation, proliferation, and isotype switching. Clonally expanded, IgG isotype-biased humoral immunity associates with favorable prognosis primarily in triple-negative breast cancers. In breast cancer, humoral immune responses may contribute to clinical outcomes, especially in more immunogenic subtypes. Here, we investigated B lymphocyte subsets, immunoglobulin expression, and clonal features in breast tumors, focusing on aggressive triple-negative breast cancers (TNBC). In samples from patients with TNBC and healthy volunteers, circulating and tumor-infiltrating B lymphocytes (TIL-B) were evaluated. CD20+CD27+IgD− isotype-switched B lymphocytes were increased in tumors, compared with matched blood. TIL-B frequently formed stromal clusters with T lymphocytes and engaged in bidirectional functional cross-talk, consistent with gene signatures associated with lymphoid assembly, costimulation, cytokine–cytokine receptor interactions, cytotoxic T-cell activation, and T-cell–dependent B-cell activation. TIL-B–upregulated B-cell receptor (BCR) pathway molecules FOS and JUN, germinal center chemokine regulator RGS1, activation marker CD69, and TNFα signal transduction via NFκB, suggesting BCR–immune complex formation. Expression of genes associated with B lymphocyte recruitment and lymphoid assembly, including CXCL13, CXCR4, and DC-LAMP, was elevated in TNBC compared with other subtypes and normal breast. TIL-B–rich tumors showed expansion of IgG but not IgA isotypes, and IgG isotype switching positively associated with survival outcomes in TNBC. Clonal expansion was biased toward IgG, showing expansive clonal families with specific variable region gene combinations and narrow repertoires. Stronger positive selection pressure was present in the complementarity determining regions of IgG compared with their clonally related IgA in tumor samples. Overall, class-switched B lymphocyte lineage traits were conspicuous in TNBC, associated with improved clinical outcomes, and conferred IgG-biased, clonally expanded, and likely antigen-driven humoral responses. Tumor-infiltrating B lymphocytes assemble in clusters, undergoing B-cell receptor–driven activation, proliferation, and isotype switching. Clonally expanded, IgG isotype-biased humoral immunity associates with favorable prognosis primarily in triple-negative breast cancers.