Mazor Roei D, Nathan Nachum, Gilboa Amit, Stoler-Barak Liat, Moss Lihee, Solomonov Inna, Hanuna Assaf, Divinsky Yalin, Shmueli Merav D, Hezroni Hadas, Zaretsky Irina, Mor Michael, Golani Ofra, Sabah Gad, Jakobson-Setton Ariella, Yanichkin Natalia, Feinmesser Meora, Tsoref Daliah, Salman Lina, Yeoshoua Effi, Peretz Eyal, Erlich Inna, Cohen Netta Mendelson, Gershoni Jonathan M, Freund Natalia, Merbl Yifat, Yaari Gur, Eitan Ram, Sagi Irit, Shulman Ziv
Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel.
Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.
Cell. 2022 Mar 31;185(7):1208-1222.e21. doi: 10.1016/j.cell.2022.02.012. Epub 2022 Mar 18.
The tumor microenvironment hosts antibody-secreting cells (ASCs) associated with a favorable prognosis in several types of cancer. Patient-derived antibodies have diagnostic and therapeutic potential; yet, it remains unclear how antibodies gain autoreactivity and target tumors. Here, we found that somatic hypermutations (SHMs) promote antibody antitumor reactivity against surface autoantigens in high-grade serous ovarian carcinoma (HGSOC). Patient-derived tumor cells were frequently coated with IgGs. Intratumoral ASCs in HGSOC were both mutated and clonally expanded and produced tumor-reactive antibodies that targeted MMP14, which is abundantly expressed on the tumor cell surface. The reversion of monoclonal antibodies to their germline configuration revealed two types of classes: one dependent on SHMs for tumor binding and a second with germline-encoded autoreactivity. Thus, tumor-reactive autoantibodies are either naturally occurring or evolve through an antigen-driven selection process. These findings highlight the origin and potential applicability of autoantibodies directed at surface antigens for tumor targeting in cancer patients.
肿瘤微环境中存在与多种癌症预后良好相关的抗体分泌细胞（ASC）。患者来源的抗体具有诊断和治疗潜力；然而，抗体如何获得自身反应性并靶向肿瘤仍不清楚。在这里，我们发现体细胞超突变（SHM）促进了高级别浆液性卵巢癌（HGSOC）中抗体对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覆盖。HGSOC中的肿瘤内ASC发生了突变并克隆性扩增，并产生了靶向MMP14的肿瘤反应性抗体，MMP14在肿瘤细胞表面大量表达。单克隆抗体回复到其胚系构型后显示出两种类型：一种依赖SHM进行肿瘤结合，另一种具有胚系编码的自身反应性。因此，肿瘤反应性自身抗体要么是天然存在的，要么是通过抗原驱动的选择过程进化而来的。这些发现突出了针对癌症患者肿瘤靶向的表面抗原的自身抗体的起源和潜在适用性。
