Translational Computational Immunologist Massachusetts Gen. Hosp., Harvard Med. Sch., United States
Disclosure(s):
Sergio Aguilar Fernandez, PhD: No financial relationships to disclose
Introduction/Rationale: Immune checkpoint blockade potentiates antitumor responses but can also disrupt immune tolerance, provoking immune-related adverse events (irAEs). These toxicities reflect systemic immune dysregulation, yet their cellular and molecular determinants remain poorly defined. Understanding their basis is essential to identify at-risk patients and guide safer immunotherapy strategies. Given its accessibility and ability to capture systemic immune activity, blood provides a clinically actionable platform to define programs shared and distinct between irAEs and related autoimmune diseases, enabling nomination of potential biomarkers and therapeutic targets.
Methods: We profiled peripheral blood mononuclear cells from >200 cancer patients receiving ICI therapy, including irMyocarditis, irArthritis, irColitis, irHepatitis, irNephritis, irNeurotoxicity, irThyroiditis, irDiabetes, and irPneumonitis, together with ICI-treated controls without toxicity, using scRNA-seq, CITE-seq, and TCR-seq. We further integrated PBMCs from autoimmune disease cohorts affecting the same organ systems, generating a cross-disease dataset of ~5 million cells from ~400 donors.
Results: Integrative analyses revealed immune programs shared and distinct across irAEs and autoimmune counterparts. Expansion of inflammatory subsets and upregulation of activation and trafficking programs were observed across multiple lineages. TCR-seq linked clonally expanded effector T cells with inflammatory signatures common to irAEs and autoimmunity. Multi-omic integration identified convergent gene programs and signaling pathways, advancing mechanistic understanding and highlighting therapeutic opportunities.
Conclusion: Circulating immune states define systemic programs underlying irAEs, some overlapping with autoimmunity. These findings reveal blood biomarkers and immune circuits that nominate tractable therapeutic targets, enhancing the safety and precision of checkpoint immunotherapy and supporting minimally invasive monitoring of immune toxicity.
