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

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.

Keywords: B cells; HGSOC; MMP14; MT1-MMP; antibodies; antibody-mediated immune response; autoantibodies; cancer; ovarian cancer; plasma cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal
  • Antibodies, Neoplasm*
  • Autoantibodies
  • Autoantigens
  • Female
  • Humans
  • Ovarian Neoplasms* / genetics
  • Tumor Microenvironment


  • Antibodies, Monoclonal
  • Antibodies, Neoplasm
  • Autoantibodies
  • Autoantigens