Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
Nature. 2021 Sep;597(7875):274-278. doi: 10.1038/s41586-020-2931-3. Epub 2020 Nov 18.
Tumours often contain B cells and plasma cells but the antigen specificity of these intratumoral B cells is not well understood. Here we show that human papillomavirus (HPV)-specific B cell responses are detectable in samples from patients with HPV-positive head and neck cancers, with active production of HPV-specific IgG antibodies in situ. HPV-specific antibody secreting cells (ASCs) were present in the tumour microenvironment, with minimal bystander recruitment of influenza-specific cells, suggesting a localized and antigen-specific ASC response. HPV-specific ASC responses correlated with titres of plasma IgG and were directed against the HPV proteins E2, E6 and E7, with the most dominant response against E2. Using intratumoral B cells and plasma cells, we generated several HPV-specific human monoclonal antibodies, which exhibited a high degree of somatic hypermutation, consistent with chronic antigen exposure. Single-cell RNA sequencing analyses detected activated B cells, germinal centre B cells and ASCs within the tumour microenvironment. Compared with the tumour parenchyma, B cells and ASCs were preferentially localized in the tumour stroma, with well-formed clusters of activated B cells indicating ongoing germinal centre reactions. Overall, we show that antigen-specific activated and germinal centre B cells as well as plasma cells can be found in the tumour microenvironment. Our findings provide a better understanding of humoral immune responses in human cancer and suggest that tumour-infiltrating B cells could be harnessed for the development of therapeutic agents.
肿瘤中通常含有 B 细胞和浆细胞，但这些肿瘤内 B 细胞的抗原特异性尚不清楚。在这里，我们表明在 HPV 阳性头颈部癌症患者的样本中可检测到 HPV 特异性 B 细胞反应，并且原位产生 HPV 特异性 IgG 抗体。HPV 特异性抗体分泌细胞（ASC）存在于肿瘤微环境中，仅有少量流感特异性细胞的旁观者募集，表明存在局部和抗原特异性 ASC 反应。HPV 特异性 ASC 反应与血浆 IgG 滴度相关，并针对 HPV 蛋白 E2、E6 和 E7 进行反应，最主要的反应针对 E2。使用肿瘤内 B 细胞和浆细胞，我们生成了几种 HPV 特异性人源单克隆抗体，这些抗体表现出高度的体细胞超突变，与慢性抗原暴露一致。单细胞 RNA 测序分析在肿瘤微环境中检测到活化的 B 细胞、生发中心 B 细胞和 ASC。与肿瘤实质相比，B 细胞和 ASC 优先定位于肿瘤基质中，形成活化 B 细胞的良好簇表明正在进行生发中心反应。总体而言，我们表明抗原特异性活化和生发中心 B 细胞以及浆细胞可存在于肿瘤微环境中。我们的研究结果提供了对人类癌症中体液免疫反应的更好理解，并表明肿瘤浸润 B 细胞可被用于开发治疗剂。
