CTLA-4 Pathway Is Instrumental in Giant Cell Arteritis

Paul Régnier , Alexandre Le Joncour , Anna Maciejewski-Duval , Guillaume Darrasse-Jèze , Charles Dolladille , Wouter C Meijers , Lisa Bastarache , Pierre Fouret , Patrick Bruneval , Floriane Arbaretaz , Célia Sayetta , Ana Márquez , Michelle Rosenzwajg (1, 2) , David Klatzmann , Patrice Cacoub , Javid J Moslehi , Joe-Elie Salem (3) , David Saadoun

1 I3 - Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière]
2 CIC-BTi - Centre d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière]
3 CHU Pitié-Salpêtrière [AP-HP]

BACKGROUND: Giant cell arteritis (GCA) causes severe inflammation of the aorta and its branches and is characterized by intense effector T-cell infiltration. The roles that immune checkpoints play in the pathogenesis of GCA are still unclear. Our aim was to study the immune checkpoint interplay in GCA. METHODS: First, we used VigiBase, the World Health Organization international pharmacovigilance database, to evaluate the relationship between GCA occurrence and immune checkpoint inhibitors treatments. We then further dissected the role of immune checkpoint inhibitors in the pathogenesis of GCA, using immunohistochemistry, immunofluorescence, transcriptomics, and flow cytometry on peripheral blood mononuclear cells and aortic tissues of GCA patients and appropriated controls. RESULTS: Using VigiBase, we identified GCA as a significant immune-related adverse event associated with anti-CTLA-4 (cytotoxic T-lymphocyte–associated protein-4) but not anti-PD-1 (anti-programmed death-1) nor anti-PD-L1 (anti-programmed death-ligand 1) treatment. We further dissected a critical role for the CTLA-4 pathway in GCA by identification of the dysregulation of CTLA-4–derived gene pathways and proteins in CD4 + (cluster of differentiation 4) T cells (and specifically regulatory T cells) present in blood and aorta of GCA patients versus controls. While regulatory T cells were less abundant and activated/suppressive in blood and aorta of GCA versus controls, they still specifically upregulated CTLA-4. Activated and proliferating CTLA-4 + Ki-67 + regulatory T cells from GCA were more sensitive to anti-CTLA-4 (ipilimumab)–mediated in vitro depletion versus controls. CONCLUSIONS: We highlighted the instrumental role of CTLA-4 immune checkpoint in GCA, which provides a strong rationale for targeting this pathway.

Mots clés: giant cell arteritis ◼ humans ◼ immune checkpoint inhibitors ◼ T-lymphocytes; regulatory ◼ vasculitis

Domaines: Sciences du Vivant [q-bio]

Paul Régnier, Alexandre Le Joncour, Anna Maciejewski-Duval, Guillaume Darrasse-Jèze, Charles Dolladille, et al.. CTLA-4 Pathway Is Instrumental in Giant Cell Arteritis. Circulation Research, 2023, 133 (4), pp.298-312. ⟨10.1161/circresaha.122.322330⟩. ⟨hal-04289514⟩