Atreca, Inc., 500 Saginaw Dr., Redwood City, CA 94063, USA.
California Pacific Medical Center Research Institute, 2200 Webster St., San Francisco, CA 94115, USA.
Clin Immunol. 2018 Feb;187:37-45. doi: 10.1016/j.clim.2017.10.002. Epub 2017 Oct 12.
There is significant debate regarding whether B cells and their antibodies contribute to effective anti-cancer immune responses. Here we show that patients with metastatic but non-progressing melanoma, lung adenocarcinoma, or renal cell carcinoma exhibited increased levels of blood plasmablasts. We used a cell-barcoding technology to sequence their plasmablast antibody repertoires, revealing clonal families of affinity matured B cells that exhibit progressive class switching and persistence over time. Anti-CTLA4 and other treatments were associated with further increases in somatic hypermutation and clonal family size. Recombinant antibodies from clonal families bound non-autologous tumor tissue and cell lines, and families possessing immunoglobulin paratope sequence motifs shared across patients exhibited increased rates of binding. We identified antibodies that caused regression of, and durable immunity toward, heterologous syngeneic tumors in mice. Our findings demonstrate convergent functional anti-tumor antibody responses targeting public tumor antigens, and provide an approach to identify antibodies with diagnostic or therapeutic utility.
关于 B 细胞及其抗体是否有助于有效的抗肿瘤免疫反应，存在很大的争议。在这里，我们发现患有转移性但无进展的黑色素瘤、肺腺癌或肾细胞癌的患者血液中的浆母细胞水平升高。我们使用细胞条形码技术对其浆母细胞抗体库进行测序，揭示了亲和力成熟的 B 细胞的克隆家族，这些家族随着时间的推移表现出逐渐的类别转换和持续存在。抗 CTLA4 及其他治疗方法与体细胞超突变和克隆家族大小的进一步增加有关。来自克隆家族的重组抗体与非自体肿瘤组织和细胞系结合，并且在不同患者之间共享免疫球蛋白变区序列基序的家族表现出更高的结合率。我们鉴定出了能够引起同种异体同源肿瘤在小鼠中消退并产生持久免疫的抗体。我们的研究结果表明存在针对公共肿瘤抗原的趋同功能抗肿瘤抗体反应，并提供了一种识别具有诊断或治疗效用的抗体的方法。
