Background/Purpose: The use of anti-PD-1 (aPD-1) immunotherapy has seen significant success in clinical practice, corresponding with a continued rise in clinical indications for multiple cancer diagnoses. Immune-related adverse events (irAEs) are a type of secondary autoimmune toxicities arising in the setting of cancer immunotherapy. They can cause significant morbidity and disruption of the treatment of oncologic patients. They also offer a controlled setting for dissecting the cellular and signaling networks of autoimmunity development.

Methods: To better understand irAEs in the setting of aPD-1 immunotherapy, we established a prospective, longitudinal cohort at the University of Pennsylvania enrolling patients before immunotherapy and following them for a year. We stratified the responses in two groups: patients that developed at least one irAE event (irAE⁺) and patients that never developed an irAE event (irAE^–) during that time period.

Results: Using high-dimensional cytometry, we found that irAE⁺ patients had a larger increase in their activated CD4 T cells after PD-1 inhibition compared to irAE^– patients. In addition, plasmablast generation following immunotherapy was higher for irAE⁺ patients. Using PhIP-Seq, an autoantigen screening assay, we found that irAE⁺ patients demonstrated robust enrichment in autoantibodies against various tissue antigens after immunotherapy with unique patterns for each patient. Finally, a large-scale proteomic analysis revealed that irAE⁺ patients at baseline have increased levels of circulating inflammatory mediators.

Conclusion: These results indicate that there are distinct cellular and serological imprints of irAE⁺ patients that reflect their heightened autoimmune reactivity and can be used to uncover the underlying pathogenic mechanism of irAEs and design predictive algorithms.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/unique-cellular-and-autoantibody-signatures-in-patients-with-iraes-revealed-by-longitudinal-immune-tracking/