Tumours often contain B cells and plasma cells but the antigen specificity of these intratumoral B cells is not well understood 1 – 8 . 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. Detailed analyses of B cells in the tumour microenvironment of human papilloma virus (HPV)-linked head and neck cancers reveal strong humoral immune responses to HPV antigens and the secretion of HPV-specific antibodies in situ.

中文翻译：

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定义头颈癌患者的 HPV 特异性 B 细胞反应

肿瘤通常含有 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 1 – 8 。在这里，我们表明在 HPV 阳性头颈癌患者的样本中可检测到人乳头瘤病毒 (HPV) 特异性 B 细胞反应，并且原位主动产生 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，流感特异性细胞的旁观者募集最少，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，其中针对 E2 的反应最为显着。使用肿瘤内 B 细胞和浆细胞，我们产生了几种 HPV 特异性人单克隆抗体，它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 测序分析检测到肿瘤微环境中的活化 B 细胞、生发中心 B 细胞和 ASC。与肿瘤实质相比，B 细胞和 ASCs 优先定位在肿瘤基质中，形成良好的活化 B 细胞簇表明正在进行的生发中心反应。总体而言，我们表明在肿瘤微环境中可以发现抗原特异性活化和生发中心 B 细胞以及浆细胞。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，并表明可以利用肿瘤浸润性 B 细胞来开发治疗剂。