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

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 YeoshouaEyal Peretz, Inna Erlich, Netta Mendelson Cohen, Jonathan M. Gershoni, Natalia Freund, Yifat Merbl, Gur Yaari, Ram Eitan, Irit Sagi*, Ziv Shulman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1208-1222.e21
JournalCell
Volume185
Issue number7
DOIs
StatePublished - 31 Mar 2022

Keywords

  • B cells
  • HGSOC
  • MMP14
  • MT1-MMP
  • antibodies
  • antibody-mediated immune response
  • autoantibodies
  • cancer
  • ovarian cancer
  • plasma cells

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