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

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Antibody-secreting cells (ASCs) in the tumor microenvironment correlate with better prognoses in various cancers.
• The mechanisms by which antibodies acquire tumor-targeting (autoreactivity) capabilities remain largely unknown.
• Patient-derived antibodies hold promise for cancer diagnostics and therapeutics.

Purpose of the Study:

• To investigate the role of somatic hypermutations (SHMs) in generating antitumor antibody reactivity.
• To identify the origin and characteristics of autoantibodies targeting tumors in high-grade serous ovarian carcinoma (HGSOC).
• To explore the potential of tumor-reactive autoantibodies for cancer treatment.

Main Methods:

• Analysis of intratumoral ASCs from HGSOC patients.
• Assessment of IgG coating on patient-derived tumor cells.
• Mutation and clonal expansion analysis of ASCs.
• Characterization of tumor-reactive antibodies targeting surface autoantigens like MMP14.
• Reversion of monoclonal antibodies to their germline configuration.

Main Results:

• Patient-derived tumor cells in HGSOC were frequently coated with IgGs.
• Intratumoral ASCs showed mutations and clonal expansion, producing antibodies targeting the surface autoantigen MMP14.
• Two classes of antibodies were identified: those requiring SHMs for tumor binding and those with inherent germline autoreactivity.
• These findings indicate that tumor-reactive autoantibodies can be naturally occurring or evolve via antigen-driven selection.

Conclusions:

• Somatic hypermutations are a key mechanism promoting antibody antitumor reactivity against surface autoantigens in HGSOC.
• Tumor-reactive autoantibodies arise either naturally or through an antigen-driven evolutionary process.
• Understanding the origin of these autoantibodies provides insights into their potential application for surface antigen-targeted cancer therapy.