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Tu204 - Clonally Expanded cd38hi Cytotoxic CD8 T Cells Define the T Cell Infiltrate in Checkpoint Inhibitor-associated Arthritis

Tuesday, June 20, 2023
6:00 PM – 7:45 PM  
Anvita Singaraju – Weill Cornell Graduate School of Medical Sciences – Hospital for Special Surgery; Runci Wang – Department of Rheumatology and Immunology – Shanghai Jiaotong University School of Medicine; Lorien Shakib – Weill Cornell Graduate School of Medical Sciences – Hospital for Special Surgery; Garrett Dunlap – Brigham and Women’s Hospital and Harvard Medical School; Stinne Greisen – Aarhus University Hospital; Lin Chen – Brigham and Women’s Hospital and Harvard Medical School; Aidan Tirpack – Hospital for Special Surgery / Weill Cornell Medicine; Miriam Fein – Hospital for Special Surgery; Ifeoluwakiisi Adejoorin – Brigham and Women's Hospital; Derrick Todd – Brigham and Women’s Hospital and Harvard Medical School; Lindsey MacFarlane – Brigham and Women’s Hospital and Harvard Medical School; Susan Goodman – Hospital for Special Surgery / Weill Cornell Medicine; Edward DiCarlo – Hospital for Special Surgery / Weill Cornell Medicine; Elena Massarotti – Brigham and Women’s Hospital and Harvard Medical School; Jeffrey Sparks – Brigham and Women’s Hospital and Harvard Medical School; Anna Helena Jonsson – Brigham and Women’s Hospital and Harvard Medical School; Michael Brenner – Brigham and Women’s Hospital and Harvard Medical School; Michael Postow – Memorial Sloan Kettering Cancer Center; Karmela Kim Chan – Hospital for Special Surgery / Weill Cornell Medicine; Anne Bass – Hospital for Special Surgery / Weill Cornell Medicine; Laura Donlin – Hospital for Special Surgery / Weill Cornell Medicine; Deepak Rao – Brigham and Women’s Hospital and Harvard Medical School
Abstract Text: Immune checkpoint inhibitor (ICI) therapies used to treat cancer, such as anti-PD1 and anti-CTLA-4 antibodies, can induce a range of immune-related adverse events (irAEs) including ICI-arthritis. To assess the T cell response of ICI-arthritis and how it overlaps with spontaneous autoimmune diseases, we compared T cells from joints of twenty patients with ICI-arthritis to two archetypal autoimmune arthritides, rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Single cell transcriptomic and TCR repertoire analyses highlighted clonal expansion of an activated effector CD8 T cell population in joints and blood of ICI-arthritis patients. These CD8 T cells, identified as CD38hiCD127-, were uniquely enriched in ICI-arthritis joints compared to RA and PsA and displayed an elevated interferon signature. In vitro, type I interferon induced CD8 T cells to acquire the ICI-associated CD38hi phenotype and boosted cytotoxic function in a novel cytotoxicity assay. In a cohort of patients with advanced melanoma (n=31 pairs), ICI therapy dramatically expanded circulating CD38hiCD127- CD8 T cells, more so than any other T cell population. These CD38hiCD127- CD8 T cells were Ki67+ and frequently bound by the therapeutic anti-PD-1 drug. TCR sequencing of paired blood and synovial fluid T cells from ICI arthritis patients revealed anti-PD-1 drug-bound CD8 T cells in synovial fluid had marked clonal overlap with drug-bound CD8 T cells in circulation but almost no overlap with non-drug-bound CD8 T cells in circulation. These results suggest ICI therapy directly targets CD8 T cells in patients with ICI-arthritis to induce a novel autoimmune pathology distinct from spontaneous autoimmune arthritides.