小柯机器人

以色列魏茨曼科学研究所Ziv Shulman、Irit Sagi等研究人员合作发现，肿瘤反应性抗体由非结合的和自身反应的前体演化而来。这一研究成果于2022年3月18日在线发表于国际学术期刊《细胞》。

研究人员发现体细胞高突变（SHM）促进抗体对高级别浆液性卵巢癌（HGSOC）表面自身抗原的抗肿瘤反应性。患者来源的肿瘤细胞经常被IgG包裹。HGSOC瘤内的抗体分泌细胞（ASC）既突变又克隆扩增，并产生针对MMP14的肿瘤反应性抗体，而MMP14在肿瘤细胞表面大量表达。通过将单克隆抗体还原为其种系配置，研究人员发现有两种类型：一种是依赖于SHM的肿瘤结合，另一种是具有种系编码的自反应性。因此，肿瘤反应性的自身抗体要么是自然发生的，要么是通过抗原驱动的选择过程演化的。这些发现强调了针对表面抗原的自身抗体的起源和潜在的适用性，有望用于癌症患者的肿瘤靶向。

据悉，肿瘤微环境承载着ASC，与几种类型的癌症的有利预后有关。患者产生的抗体具有诊断和治疗的潜力；然而，目前仍不清楚抗体如何获得自反应性和针对肿瘤。

附：英文原文

Title: Tumor-reactive antibodies evolve from non-binding and autoreactive precursors

Author: Roei D. Mazor, Nachum Nathan, Amit Gilboa, Liat Stoler-Barak, Lihee Moss, Inna Solomonov, Assaf Hanuna, Yalin Divinsky, Merav D. Shmueli, Hadas Hezroni, Irina Zaretsky, Michael Mor, Ofra Golani, Gad Sabah, Ariella Jakobson-Setton, Natalia Yanichkin, Meora Feinmesser, Daliah Tsoref, Lina Salman, Effi Yeoshoua, Eyal Peretz, Inna Erlich, Netta Mendelson Cohen, Jonathan M. Gershoni, Natalia Freund, Yifat Merbl, Gur Yaari, Ram Eitan, Irit Sagi, Ziv Shulman

Issue&Volume: 2022-03-18

Abstract: The tumor microenvironment hosts antibody-secreting cells (ASCs) associated with afavorable prognosis in several types of cancer. Patient-derived antibodies have diagnosticand therapeutic potential; yet, it remains unclear how antibodies gain autoreactivityand target tumors. Here, we found that somatic hypermutations (SHMs) promote antibodyantitumor reactivity against surface autoantigens in high-grade serous ovarian carcinoma(HGSOC). Patient-derived tumor cells were frequently coated with IgGs. IntratumoralASCs in HGSOC were both mutated and clonally expanded and produced tumor-reactiveantibodies that targeted MMP14, which is abundantly expressed on the tumor cell surface.The reversion of monoclonal antibodies to their germline configuration revealed twotypes of classes: one dependent on SHMs for tumor binding and a second with germline-encodedautoreactivity. Thus, tumor-reactive autoantibodies are either naturally occurringor evolve through an antigen-driven selection process. These findings highlight theorigin and potential applicability of autoantibodies directed at surface antigensfor tumor targeting in cancer patients.

DOI: 10.1016/j.cell.2022.02.012

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00192-1