Recently, a research team led by Aaron M. Ring of the Fred Hutchinson Cancer Research Center, Harriet M. Kluger of the Yale University School of Medicine, and Leon Furchtgott of the biotechnology company Seranova Bio published a major study in the top journal Nature.
They discovered that certain autoantibodies in cancer patients are closely associated with the effectiveness of immunotherapy. The presence of some autoantibodies increases a patient's likelihood of responding to immunotherapy by 5-10 times. It's no wonder that some patients respond so well to immunotherapy, while others do poorly. Autoantibodies may be the key drivers behind this.
In the short term, these autoantibodies have the potential to become biomarkers predicting immunotherapy efficacy. More importantly, the antigens targeted by these autoantibodies have the potential to become new drug development targets to improve immunotherapy efficacy.
When we talk about immunotherapy, we often think of T cells, along with macrophages, neutrophils, and dendritic cells. B cells, which are involved in humoral immunity, are rarely mentioned. In recent years, studies have shown that B cells, particularly the tertiary lymphoid structures containing them, are closely linked to the effectiveness of cancer immunotherapy. B cells are actually versatile, not only presenting antigens to T cells but also producing antibodies that contribute to anti-tumor immunity.
As early as the late 20th century, studies have shown that autoantibodies (AAbs) targeting tumor antigens such as HER2 and MUC1 are associated with improved survival in cancer patients. However, the relationship between autoantibodies in cancer patients and immunotherapy has not been systematically or comprehensively studied.
About three years ago, Aaron M. Ring's team developed a new high-throughput technology—Rapid Extracellular Antigen Assay (REAP)—that allows researchers to simultaneously detect autoantibodies against thousands of human extracellular and secreted proteins. With this powerful tool, they sought to determine whether autoantibodies in cancer patients enhance or diminish the effects of immunotherapy. Powered by REAP, researchers analyzed plasma samples from 374 cancer patients receiving immune checkpoint inhibitor therapy (PD-1 or PD-L1 inhibitors alone, and PD-1 inhibitors combined with CTLA-4 inhibitors) and 131 healthy controls. They detected 2,922 unique autoantibodies targeting the extracellular proteome in this cohort. Most autoantibodies were rare, detected in less than 1% of all samples. However, blood samples collected before immunotherapy showed elevated autoantibody levels and a unique autoantibody signature.
Figure 1. Global features of the extracellular AAb reactome in patients treated with CPIs. (Dai Y, et al., 2025)
The researchers then analyzed the relationship between autoantibodies and immunotherapy response. They found that patients who responded to immunotherapy had elevated levels of autoantibodies targeting inflammatory cytokines such as IL-6, IL-17, and IFN-I. This finding is consistent with previous research linking these inflammatory cytokines to immunosuppression. Among these inflammatory cytokines, IFN-I was the most prominent. Autoantibodies targeting a broad range of IFN-I proteins (such as IFNα2, IFNα4, and IFNα8) were most significantly associated with immunotherapy response. In contrast, in blood samples from patients who did not respond to immunotherapy, autoantibodies targeting IFN-I were limited to a single IFN-I protein and were present at relatively low levels.
Studies based on mouse models have shown that administering antibodies targeting the IFN-I receptor or broadly neutralizing mouse IFN-I proteins enhances the efficacy of immunotherapy, even in immunotherapy-resistant mice. Histological analysis also revealed an increase in the proportion of polyfunctional CD8-positive T cells producing IFNγ and TNF in mice treated with pan-IFN-I neutralizing antibodies.
Notably, they also discovered a novel target previously unreported for immunotherapy: TL1A. Autoantibodies neutralizing TL1A were found at elevated levels in samples from patients responding to immunotherapy. Blocking TL1A in combination with PD-1 inhibitors can enhance the therapeutic efficacy of PD-1 inhibitors. Furthermore, the study found that autoantibodies targeting signaling pathways such as IFN-I and IFN-III consistently predicted immunotherapy response across different cancer types. Finally, they analyzed the relationship between autoantibodies and immune-related adverse events of immunotherapy, finding no significant correlation.
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Overall, this research reveals a deeper interplay between humoral immunity and checkpoint inhibitors than previously appreciated. This discovery not only helps identify cancer patients most likely to benefit from immunotherapy but also aids the development of new drugs that enhance the effectiveness of immunotherapy.
Reference
Dai Y, et al. Humoral determinants of checkpoint immunotherapy. Nature, 2025: 1-10.