Undergraduate Immunology Researcher Vanderbilt Univ. Med. Ctr. Brentwood, Tennessee, United States
Introduction/Rationale: Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of melanoma and other cancers but can cause immune-related adverse events (irAEs) and lasting autoimmune tissue damage. One such irAE (ICI-sicca) shares some features with the rheumatic disease, Sjӧgren’s syndrome, with dry mouth being the symptom typically reported by ICI-sicca patients. A fraction of ICI-sicca patients have Sjӧgren’s-associated autoantibodies, signifying autoreactive B cell activity in this disease.
Methods: To identify B cell gene dysregulation that arises with ICI-sicca onset, we used single-cell RNA-sequencing to compare CD19+ cells isolated from peripheral blood collected 3-4 weeks after ICI therapy initiation (pre-ICI sicca) or following ICI-sicca symptom onset (post-ICI sicca) in n = 6 melanoma patients. Transcriptome-based clustering using Seurat identified n = 14 clusters, which we manually collapsed into five major B cell subsets (transitional, naïve, activated, memory, and plasmablasts).
Results: We observed upregulation of genes following ICI-sicca development in naïve (n = 1296 genes), activated (n = 42 genes), and memory (n = 775 genes) B cell subsets, relative to the pre-ICI sicca timepoint, based on adjusted p-value < 0.05 and fold change > 1.2 cutoffs. These upregulated genes were related to BCR signaling, actin cytoskeleton rearrangement, antigen processing and presentation, and interferon responses.
Conclusion: Some of the ICI-sicca upregulated genes were also noted to be increased in rheumatic disease patients relative to healthy controls in other single-cell RNA-seq studies performed by our lab, suggesting the potential for shared B cell liability across spontaneous and ICI-induced autoimmunity. Future studies will validate alteration of these key B cell functions and explore pharmacologic methods to restore this aberrant B cell rewiring as a means to generate new hypotheses that can be tested with the ultimate goal of limiting ICI sicca, and potentially other irAE development.
