小柯机器人

2021年2月3日，美国H. Lee Moffitt癌症研究中心Jose R. Conejo-Garcia团队在《自然》杂志发表论文发现，IgA转胞吞作用和抗原识别调控卵巢癌免疫。

通过3个独立队列，总共534例高度浆液性卵巢癌患者，研究人员发现强大的保护性体液反应以多克隆IgA的产生为主导，该多克隆IgA与在卵巢癌细胞上普遍表达的多聚IgA受体结合。值得注意的是，源自肿瘤B细胞的IgA使得髓样细胞抵御细胞外的致癌驱动因子，从而导致肿瘤细胞死亡。另外，通过恶性上皮细胞的IgA转胞吞作用引起转录变化，其拮抗RAS途径并使肿瘤细胞对T细胞的细胞杀伤作用敏感，这也有助于阻止恶性进展。因此，肿瘤抗原特异性和抗原非依赖性IgA应答通过控制协调的肿瘤细胞、T细胞和B细胞应答来拮抗卵巢癌的生长。

这些发现为鉴定被肿瘤内B细胞源性抗体自发识别的靶标提供了平台，并且表明增强B细胞反应的免疫疗法可能比专注于T细胞的方法更有效，尤其是对于检查点抑制剂具有抗性的恶性肿瘤。 

据悉，大多数卵巢癌均被预后相关的活化T细胞浸润，但对免疫检查点抑制剂的应答率却较低。以前，记忆B细胞和浆细胞浸润被发现与卵巢癌的预后更相关，但这些反应的性质和功能相关性尚存争议。

附：英文原文

Title: IgA transcytosis and antigen recognition govern ovarian cancer immunity

Author: Subir Biswas, Gunjan Mandal, Kyle K. Payne, Carmen M. Anadon, Chandler D. Gatenbee, Ricardo A. Chaurio, Tara Lee Costich, Carlos Moran, Carly M. Harro, Kristen E. Rigolizzo, Jessica A. Mine, Jimena Trillo-Tinoco, Naoko Sasamoto, Kathryn L. Terry, Douglas Marchion, Andrea Buras, Robert M. Wenham, Xiaoqing Yu, Mary K. Townsend, Shelley S. Tworoger, Paulo C. Rodriguez, Alexander R. Anderson, Jose R. Conejo-Garcia

Issue&Volume: 2021-02-03

Abstract: Most ovarian cancers are infiltrated by prognostically relevant activated T cells1,2,3, yet exhibit low response rates to immune checkpoint inhibitors4. Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer5,6, but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors.

DOI: 10.1038/s41586-020-03144-0

Source: https://www.nature.com/articles/s41586-020-03144-0

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html