Humoral determinants of checkpoint immunotherapy

Yile Dai, Lilach Aizenbud, Kai Qin, Matthew Austin, Jillian R. Jaycox, Joseph Cunningham, Eric Y. Wang, Lin Zhang, Suzanne Fischer, Sean M. Carroll, Helen Aggelen, Yuval Kluger, Kevan C. Herold, Leon Furchtgott (), Harriet M. Kluger () and Aaron M. Ring ()
Additional contact information
Yile Dai: Yale School of Medicine
Lilach Aizenbud: Yale Cancer Center
Kai Qin: Fred Hutchinson Cancer Center
Matthew Austin: Yale Cancer Center
Jillian R. Jaycox: Yale School of Medicine
Joseph Cunningham: Yale University
Eric Y. Wang: Yale School of Medicine
Lin Zhang: Yale Cancer Center
Suzanne Fischer: Yale School of Medicine
Sean M. Carroll: Seranova Bio
Helen Aggelen: Seranova Bio
Yuval Kluger: Yale University
Kevan C. Herold: Yale School of Medicine
Leon Furchtgott: Seranova Bio
Harriet M. Kluger: Yale Cancer Center
Aaron M. Ring: Fred Hutchinson Cancer Center

Nature, 2025, vol. 644, issue 8076, 527-536

Abstract: Abstract Although the role of cellular immunity in checkpoint immunotherapy (CPI) for cancer is well established1,2, the effect of antibody-mediated humoral immunity is comparably underexplored. Here we used rapid extracellular antigen profiling3 to map the autoantibody reactome within a cohort of 374 patients with cancer treated with CPIs and 131 healthy control participants for autoantibodies to 6,172 extracellular and secreted proteins (the ‘exoproteome’). Globally, patients with cancer treated with CPIs had diverse autoreactivities that were elevated relative to control individuals but changed minimally with treatment. Autoantibody signatures in patients treated with CPI strikingly distinguished them from healthy individuals. Although associations of specific autoantibodies with immune-related adverse events were sparse, we detected numerous individual autoantibodies that were associated with greatly altered odds ratios for response to therapy. These included autoantibodies to immunomodulatory proteins, such as cytokines, growth factors and immunoreceptors, as well as tumour surface proteins. Functional evaluation of several autoantibody responses indicated that they neutralized the activity of their target proteins, which included type I interferons (IFN-I), IL-6, OSM, TL1A, and BMPR1A and BMPR2. Modelling the effects of autoantibodies to IFN-I and TL1A in preclinical mouse tumour models resulted in enhanced CPI efficacy, consistent with their effects in patients. In conclusion, these findings indicate that autoantibodies to the exoproteome modify CPI responses and highlight therapeutically actionable pathways that can be exploited to augment immunotherapy.

Date: 2025
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DOI: 10.1038/s41586-025-09188-4

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