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Tumor Immunotherapy01:27

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Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells
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Humoral determinants of checkpoint immunotherapy.

Yile Dai1, Lilach Aizenbud2, Kai Qin3

  • 1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.

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|July 23, 2025
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Autoantibodies targeting extracellular proteins significantly impact cancer immunotherapy responses. These autoantibodies can neutralize key proteins, offering new therapeutic targets to enhance checkpoint immunotherapy efficacy.

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Area of Science:

  • Immunology
  • Oncology
  • Proteomics

Background:

  • Cellular immunity's role in cancer checkpoint immunotherapy (CPI) is established, but antibody-mediated humoral immunity's impact remains less understood.
  • Autoantibodies can influence treatment outcomes, necessitating a deeper investigation into their role in CPI.

Purpose of the Study:

  • To map the autoantibody reactome against the exoproteome in cancer patients undergoing CPI.
  • To identify specific autoantibodies associated with CPI response and immune-related adverse events.
  • To explore the functional impact of autoantibodies and their therapeutic potential.

Main Methods:

  • Utilized rapid extracellular antigen profiling to analyze autoantibodies against 6,172 extracellular and secreted proteins.
  • Compared autoantibody profiles in 374 cancer patients treated with CPIs against 131 healthy controls.
  • Performed functional evaluations and preclinical mouse models to assess autoantibody effects.

Main Results:

  • Patients on CPI exhibited distinct and elevated autoantibody profiles compared to healthy individuals.
  • Specific autoantibodies, including those targeting immunomodulatory proteins and tumor surface proteins, were associated with altered CPI response.
  • Autoantibodies against type I interferons (IFN-I) and TL1A neutralized target protein activity and enhanced CPI efficacy in preclinical models.

Conclusions:

  • Autoantibodies to the exoproteome are key modulators of checkpoint immunotherapy efficacy.
  • Identified specific autoantibodies and their neutralized targets as potential therapeutic targets to augment cancer immunotherapy.
  • Findings highlight actionable pathways for improving CPI outcomes through modulation of humoral immunity.